@article{%a1.%Y,

title = {Desmin and Plectin Recruitment to the Nucleus and Nuclei Orientation Are Lost in Emery-Dreifuss Muscular Dystrophy Myoblasts Subjected to Mechanical Stimulation},

author = {Cenni V and Evangelisti C and Santi S and Sabatelli P and Neri S and Cavallo M and Lattanzi G and Mattioli E},

url = {https://www.mdpi.com/2073-4409/13/2/162},

doi = {10.3390/cells13020162},

year  = {2024},

date = {2024-01-31},

journal = {Cells},

volume = {13},

issue = {2},

pages = {162},

abstract = {n muscle cells subjected to mechanical stimulation, LINC complex and cytoskeletal proteins are basic to preserve cellular architecture and maintain nuclei orientation and positioning. In this context, the role of lamin A/C remains mostly elusive. This study demonstrates that in human myoblasts subjected to mechanical stretching, lamin A/C recruits desmin and plectin to the nuclear periphery, allowing a proper spatial orientation of the nuclei. Interestingly, in Emery-Dreifuss Muscular Dystrophy (EDMD2) myoblasts exposed to mechanical stretching, the recruitment of desmin and plectin to the nucleus and nuclear orientation were impaired, suggesting that a functional lamin A/C is crucial for the response to mechanical strain. While describing a new mechanism of action headed by lamin A/C, these findings show a structural alteration that could be involved in the onset of the muscle defects observed in muscular laminopathies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybr,

title = {Lamin A and the LINC complex act as potential tumor suppressors in Ewing Sarcoma},

author = {Chiarini F and Paganelli F and Balestra T and Capanni C and Fazio A and Manara MC and Landuzzi L and Petrini S and Evangelisti C and Lollini PL and Martelli AM and Lattanzi G and Scotlandi K},

url = {https://www.nature.com/articles/s41419-022-04729-5},

doi = {10.1038/s41419-022-04729-5},

year  = {2022},

date = {2022-05-30},

urldate = {2022-05-30},

journal = {Cell death & disease},

volume = {13},

issue = {4},

pages = {346},

abstract = {Lamin A, a main constituent of the nuclear lamina, is involved in mechanosignaling and cell migration through dynamic interactions with the LINC complex, formed by the nuclear envelope proteins SUN1, SUN2 and the nesprins. Here, we investigated lamin A role in Ewing Sarcoma (EWS), an aggressive bone tumor affecting children and young adults. In patients affected by EWS, we found a significant inverse correlation between LMNA gene expression and tumor aggressiveness. Accordingly, in experimental in vitro models, low lamin A expression correlated with enhanced cell migration and invasiveness and, in vivo, with an increased metastatic load. At the molecular level, this condition was linked to altered expression and anchorage of nuclear envelope proteins and increased nuclear retention of YAP/TAZ, a mechanosignaling effector. Conversely, overexpression of lamin A rescued LINC complex organization, thus reducing YAP/TAZ nuclear recruitment and preventing cell invasiveness. These effects were also obtained through modulation of lamin A maturation by a statin-based pharmacological treatment that further elicited a more differentiated phenotype in EWS cells. These results demonstrate that drugs inducing nuclear envelope remodeling could be exploited to improve therapeutic strategies for EWS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1.%Ybh,

title = {The wide and growing range of lamin B-related diseases: from laminopathies to cancer. },

author = {Evangelisti C and Rusciano I and Mongiorgi S and Ramazzotti G and Lattanzi G and Manzoli L and Cocco L and Ratti S and},

url = {https://link.springer.com/article/10.1007/s00018-021-04084-2},

doi = {10.1007/s00018-021-04084-2},

year  = {2022},

date = {2022-03-21},

journal = {Cellular and molecular life sciences},

volume = {79},

number = {126},

issue = {2},

abstract = {B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scaffold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifications to generate the mature protein. B-type lamins are involved in a wide range of nuclear functions, including DNA replication and repair, regulation of chromatin and nuclear stiffness. Moreover, lamins B1 and B2 regulate several cellular processes, such as tissue development, cell cycle, cellular proliferation, senescence, and DNA damage response. During embryogenesis, B-type lamins are essential for organogenesis, in particular for brain development. As expected from the numerous and pivotal functions of B-type lamins, mutations in their genes or fluctuations in their expression levels are critical for the onset of several diseases. Indeed, a growing range of human disorders have been linked to lamin B1 or B2, increasing the complexity of the group of diseases collectively known as laminopathies. This review highlights the recent findings on the biological role of B-type lamins under physiological or pathological conditions, with a particular emphasis on brain disorders and cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y__515,

title = {GSK-3: a multifaceted player in acute leukemias},

author = {Martelli AM and Evangelisti C and Paganelli F and Chiarini F and McCubrey JA},

url = {https://www.nature.com/articles/s41375-021-01243-z},

doi = {10.1038/s41375-021-01243-z},

year  = {2021},

date = {2021-04-14},

urldate = {2021-04-14},

journal = {Leukemia},

volume = {35},

number = {1829},

issue = {7},

pages = {1842},

abstract = {Glycogen synthase kinase 3 (GSK-3) consists of two isoforms (alpha and beta) that were originally linked to glucose metabolism regulation. However, GSK-3 is also involved in several signaling pathways controlling many different key functions in healthy cells. GSK-3 is a unique kinase in that its isoforms are constitutively active, while they are inactivated mainly through phosphorylation at Ser residues by a variety of upstream kinases. In the early 1990s, GSK-3 emerged as a key player in cancer cell pathophysiology. Since active GSK-3 promotes destruction of multiple oncogenic proteins (e.g., beta-catenin, c-Myc, Mcl-1) it was considered to be a tumor suppressor. Accordingly, GSK-3 is frequently inactivated in human cancer via aberrant regulation of upstream signaling pathways. More recently, however, it has emerged that GSK-3 isoforms display also oncogenic properties, as they up-regulate pathways critical for neoplastic cell proliferation, survival, and drug-resistance. The regulatory roles of GSK-3 isoforms in cell cycle, apoptosis, DNA repair, tumor metabolism, invasion, and metastasis reflect the therapeutic relevance of these kinases and provide the rationale for combining GSK-3 inhibitors with other targeted drugs. Here, we discuss the multiple and often conflicting roles of GSK-3 isoforms in acute leukemias. We also review the current status of GSK-3 inhibitor development for innovative leukemia therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_468,

title = {B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients? },

author = {Ratti S and Lonetti A and Follo MY and Paganelli F and Martelli AM and Chiarini F and Evangelisti C},

url = {https://www.mdpi.com/2072-6694/12/12/3498},

doi = {10.3390/cancers12123498},

year  = {2020},

date = {2020-01-01},

journal = {Cancers},

volume = {12},

number = {12},

pages = {E3498},

abstract = {B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients' outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_448,

title = {Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer.},

author = {Evangelisti C and Chiarini F and Paganelli F and Marmiroli S and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488919302435?via%3Dihub},

doi = {10.1016/j.bbamcr.2019.118635},

year  = {2020},

date = {2020-01-01},

journal = {Biochimica et biophysica acta. Molecular cell research},

volume = {1867},

number = {4},

pages = {118635},

abstract = {The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells. Copyright 2019 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_449,

title = {Lamin A and Prelamin A Counteract Migration of Osteosarcoma Cells},

author = {Evangelisti C and Paganelli F and Giuntini G and Mattioli E and Cappellini A and Ramazzotti G and Faenza I and Maltarello MC and Martelli AM and Scotlandi K and Chiarini F and Lattanzi G},

url = {https://www.mdpi.com/2073-4409/9/3/774},

doi = {10.3390/cells9030774},

year  = {2020},

date = {2020-01-01},

journal = {Cells},

volume = {9},

number = {3},

pages = {774},

abstract = {A type lamins are fundamental components of the nuclear lamina. Changes in lamin A expression correlate with malignant transformation in several cancers. However, the role of lamin A has not been explored in osteosarcoma (OS). Here, we wanted to investigate the role of lamin A in normal osteoblasts (OBs) and OS cells. Thus, we studied the expression of lamin A/C in OS cells compared to OBs and evaluated the effects of lamin A overexpression in OS cell lines. We show that, while lamin A expression increases during osteoblast differentiation, all examined OS cell lines express lower lamin A levels relative to differentiated OBs. The condition of low LMNA expression confers to OS cells a significant increase in migration potential, while overexpression of lamin A reduces migration ability of OS cells. Moreover, overexpression of unprocessable prelamin A also reduces cell migration. In agreement with the latter finding, OS cells which accumulate the highest prelamin A levels upon inhibition of lamin A maturation by statins, had significantly reduced migration ability. Importantly, OS cells subjected to statin treatment underwent apoptotic cell death in a RAS-independent, lamin A-dependent manner. Our results show that pro-apoptotic effects of statins and statin inhibitory effect on OS cell migration are comparable to those obtained by prelamin A accumulation and further suggest that modulation of lamin A expression and post-translational processing can be a tool to decrease migration potential in OS cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_94,

title = {Targeting Wnt/beta-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia.},

author = {Evangelisti C and Chiarini F and Cappellini A and Paganelli F and Fini M and Santi S and Martelli AM and Neri LM and Evangelisti C},

url = {https://onlinelibrary.wiley.com/doi/full/10.1002/jcp.29429},

doi = {10.1002/jcp.29429},

year  = {2020},

date = {2020-01-01},

journal = {Journal of cellular physiology},

volume = {235},

number = {6},

pages = {5413-5428},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the clonal transformation of T-cell precursors. Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/beta-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells. Notably, beta-catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T-ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β-catenin pathway through ICG-001, a CBP/beta-catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK-474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T-ALL cells. ICG-001 and ZSTK-474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/beta-catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/beta-catenin and PI3K/Akt/mTOR pathways in T-ALL settings. Copyrights 2020 Wiley Periodicals, Inc.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_437,

title = {The Role Played by Wnt/beta-Catenin Signaling Pathway in Acute Lymphoblastic Leukemia.},

author = {Chiarini F and Paganelli F and Martelli AM and Evangelisti C},

url = {https://www.mdpi.com/1422-0067/21/3/1098},

doi = {10.3390/ijms21031098},

year  = {2020},

date = {2020-01-01},

journal = {International journal of molecular sciences},

volume = {21},

number = {3},

pages = {e1098},

abstract = {Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of ALL and toxic effects limit dose escalation of current chemotherapeutics. Therefore, the identification of novel targeted therapies to support conventional chemotherapy is required. The Wnt/β-catenin pathway is a conserved signaling axis involved in several physiological processes such as development, differentiation, and adult tissue homeostasis. As a result, deregulation of this cascade is closely related to initiation and progression of various types of cancers, including hematological malignancies. In particular, deregulation of this signaling network is involved in the transformation of healthy HSCs in leukemic stem cells (LSCs), as well as cancer cell multi-drug-resistance. This review highlights the recent findings on the role of Wnt/beta-catenin in hematopoietic malignancies and provides information on the current status of Wnt/beta-catenin inhibitors with respect to their therapeutic potential in the treatment of ALL.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_458,

title = {The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias.},

author = {Martelli AM and Paganelli F and Chiarini F and Evangelisti C and McCubrey JA},

url = {https://www.mdpi.com/2072-6694/12/2/333},

doi = {10.3390/cancers12020333},

year  = {2020},

date = {2020-01-01},

journal = {Cancers},

volume = {12},

number = {2},

pages = {e333},

abstract = {The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6alpha (ATF6alpha), and inositol-requiring enzyme-1alpha (IRE1alpha). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%u,

title = {Advances in understanding the mechanisms of evasive and innate resistance to mTOR inhibition in cancer cells.},

author = {Chiarini F and Evangelisti C and Lattanzi G and McCubrey JA and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488919300424?via%3Dihub},

doi = {10.1016/j.bbamcr.2019.03.013},

year  = {2019},

date = {2019-02-20},

journal = {Biochimica et biophysica acta. Molecular cell research},

volume = {1866},

number = {8},

pages = {1322-1337},

abstract = {The development of drug-resistance by neoplastic cells is recognized as a major cause of targeted therapy failure and disease progression. The mechanistic (previously mammalian) target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that acts as the catalytic subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. Both mTORC1 and mTORC2 play key roles in a variety of healthy cell types/tissues by regulating physiological anabolic and catabolic processes in response to external cues. However, a body of evidence identified aberrant activation of mTOR signaling as a common event in many human tumors. Therefore, mTOR is an attractive target for therapeutic targeting in cancer and this fact has driven the development of numerous mTOR inhibitors, several of which have progressed to clinical trials. Nevertheless, mTOR inhibitors have met with a very limited success as anticancer therapeutics. Among other reasons, this failure was initially ascribed to the activation of several compensatory signaling pathways that dampen the efficacy of mTOR inhibitors. The discovery of these regulatory feedback mechanisms greatly contributed to a better understanding of cancer cell resistance to mTOR targeting agents. However, over the last few years, other mechanisms of resistance have emerged, including epigenetic alterations, compensatory metabolism rewiring and the occurrence of mTOR mutations. In this article, we provide the reader with an updated overview of the mechanisms that could explain resistance of cancer cells to the various classes of mTOR inhibitors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%_33,

title = {Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer.},

author = {Evangelisti C and Chiarini F and Paganelli F and Marmiroli S and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488919302435?via%3Dihub},

doi = {10.1016/j.bbamcr.2019.118635},

year  = {2019},

date = {2019-02-21},

journal = {Biochimica et biophysica acta. Molecular cell research},

volume = {1867},

number = {4},

pages = {118635},

abstract = {The introduction of therapeutics targeting specific tumor-promoting oncogenic or non-oncogenic signaling pathways has revolutionized cancer treatment. Mechanistic (previously mammalian) target of rapamycin (mTOR), a highly conserved Ser/Thr kinase, is a central hub of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR network, one of the most frequently deregulated signaling pathways in cancer, that makes it an attractive target for therapy. Numerous mTOR inhibitors have progressed to clinical trials and two of them have been officially approved as anticancer therapeutics. However, mTOR-targeting drugs have met with a very limited success in cancer patients. Frequently, the primary impediment to a successful targeted therapy in cancer is drug-resistance, either from the very beginning of the therapy (innate resistance) or after an initial response and upon repeated drug treatment (evasive or acquired resistance). Drug-resistance leads to treatment failure and relapse/progression of the disease. Resistance to mTOR inhibitors depends, among other reasons, on activation/deactivation of several signaling pathways, included those regulated by glycogen synthase kinase-3 (GSK3), a protein that targets a vast number of substrates in its repertoire, thereby orchestrating many processes that include cell proliferation and survival, metabolism, differentiation, and stemness. A detailed knowledge of the rewiring of signaling pathways triggered by exposure to mTOR inhibitors is critical to our understanding of the consequences such perturbations cause in tumors, including the emergence of drug-resistant cells. Here, we provide the reader with an updated overview of intricate circuitries that connect mTOR and GSK3 and we relate them to the efficacy (or lack of efficacy) of mTOR inhibitors in cancer cells. Copyright 2019 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_67,

title = {New advances in targeting aberrant signaling pathways in T-cell acute lymphoblastic leukemia.},

author = {Paganelli F and Lonetti A and Anselmi L and Martelli AM and Evangelisti C and Chiarini F},

url = {https://www.sciencedirect.com/science/article/pii/S2212492619300703?via%3Dihub},

doi = {10.1016/j.jbior.2019.100649},

year  = {2019},

date = {2019-03-06},

journal = {Advances in biological regulation},

volume = {74},

pages = {100649},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disorder characterized by malignant transformation of immature progenitors primed towards T-cell development. Over the past 15 years, advances in the molecular characterization of T-ALL have uncovered oncogenic key drivers and crucial signaling pathways of this disease, opening new chances for the development of novel therapeutic strategies. Currently, T-ALL patients are still treated with aggressive therapies, consisting of high dose multiagent chemotherapy. To minimize and overcome the unfavorable effects of these regimens, it is critical to identify innovative targets and test selective inhibitors of such targets. Major efforts are being made to develop small molecules against deregulated signaling pathways, which sustain T-ALL cell growth, survival, metabolism, and drug-resistance. This review will focus on recent improvements in the understanding of the signaling pathways involved in the pathogenesis of T-ALL and on the challenging opportunities for T-ALL targeted therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y%t,

title = {The Cutting Edge: The Role of mTOR Signaling in Laminopathies.},

author = {Chiarini F and Evangelisti C and Cenni V and Fazio A and Paganelli F and Martelli AM and Lattanzi G},

doi = {10.3390/ijms20040847},

year  = {2019},

date = {2019-02-06},

journal = {International journal of molecular sciences},

volume = {20},

number = {4},

pages = {E847},

abstract = {The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes. These diseases are caused by LMNA mutations and feature altered bone turnover, metabolic dysregulation, and mild to severe segmental progeria. Different LMNA mutations cause muscular, adipose tissue and nerve pathologies in the absence of major systemic involvement. This review explores recent advances on mTOR involvement in progeroid and tissue-specific laminopathies. Indeed, hyper-activation of protein kinase B (AKT)/mTOR signaling has been demonstrated in muscular laminopathies, and rescue of mTOR-regulated pathways increases lifespan in animal models of Emery-Dreifuss muscular dystrophy. Further, rapamycin, the best known mTOR inhibitor, has been used to elicit autophagy and degradation of mutated lamin A or progerin in progeroid cells. This review focuses on mTOR-dependent pathogenetic events identified in Emery-Dreifuss muscular dystrophy, LMNA-related cardiomyopathies, Hutchinson-Gilford Progeria, mandibuloacral dysplasia, and type 2 familial partial lipodystrophy. Pharmacological application of mTOR inhibitors in view of therapeutic strategies is also discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_111,

title = {Elevated TGF beta2 serum levels in Emery-Dreifuss muscular dystrophy: implications for myocyte and tenocyte differentiation and fibrogenic processes.},

author = {Bernasconi P and Carboni N and Ricci G and Siciliano G and Politano L and Maggi L and Mongini T and Vercelli L and Rodolico C and Biagini E and Boriani G and Ruggiero L and Santoro L and Schena E and Prencipe S and Evangelisti C and Pegoraro E and Morandi L and Columbaro M and Lanzuolo C and Sabatelli P and Cavalcante P and Cappelletti C and Bonne G and Muchir A and Lattanzi G},

url = {https://www.tandfonline.com/doi/abs/10.1080/19491034.2018.1467722},

doi = {10.1080/19491034.2018.1467722},

year  = {2018},

date = {2018-02-13},

journal = {Nucleus},

volume = {25},

number = {1},

pages = {24},

abstract = {Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF beta2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF beta2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss muscular dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF beta2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF beta2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF beta2-dependent mechanisms were also determined in laminopathic cells, where TGF beta2 activated AKT/mTOR phosphorylation. These data show that TGF beta2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF beta2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_135,

title = {Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia.},

author = {Evangelisti C and Cappellini A and Oliveira M and Fragoso R and Barata JT and Bertaina A and Locatelli F and Simioni C and Neri LM and Chiarini F and Lonetti A and Buontempo F and Orsini E and Pession A and Manzoli L and Martelli AM and Evangelisti C},

url = {http://onlinelibrary.wiley.com/doi/10.1002/jcp.26135/abstract},

doi = {10.1002/jcp.26135},

year  = {2018},

date = {2018-03-23},

journal = {Journal of cellular physiology},

volume = {233},

number = {3},

pages = {1796-1811},

abstract = {Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stroma-induced DEX-resistance. Finally, gene expression analysis documented that, on one hand the combination consisting of a pan PI3K p110 inhibitor and DEX strengthened the DEX-induced up- or down-regulation of several genes involved in apoptosis, while on the other, it rescued the effects of genes that might be involved in GC-resistance. Overall, our findings strongly suggest that PI3K p110 inhibition could be a promising strategy for treating B-ALL patients by improving GC therapeutic effects and/or overcoming GC-resistance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_121,

title = {Therapeutic targeting of CK2 in acute and chronic leukemias.},

author = {Buontempo F and McCubrey JA and Orsini E and Ruzzene M and Cappellini A and Lonetti A and Evangelisti C and Chiarini F and Evangelisti C and Barata JT and Martelli AM},

url = {https://www.nature.com/articles/leu2017301},

doi = {10.1038/leu.2017.301},

year  = {2018},

date = {2018-01-11},

journal = {Leukemia},

volume = {32},

number = {1},

pages = {1-10},

abstract = {CK2 is a ubiquitously expressed, constitutively active Ser/Thr protein kinase, which is considered the most pleiotropic protein kinase in the human kinome. Such a pleiotropy explains the involvement of CK2 in many cellular events. However, its predominant roles are stimulation of cell growth and prevention of apoptosis. High levels of CK2 messenger RNA and protein are associated with CK2 pathological functions in human cancers. Over the last decade, basic and translational studies have provided evidence of CK2 as a pivotal molecule driving the growth of different blood malignancies. CK2 overexpression has been demonstrated in nearly all the types of hematological cancers, including acute and chronic leukemias, where CK2 is a key regulator of signaling networks critical for cell proliferation, survival and drug resistance. The findings that emerged from these studies suggest that CK2 could be a valuable therapeutic target in leukemias and supported the initiation of clinical trials using CK2 antagonists. In this review, we summarize the recent advances on the understanding of the signaling pathways involved in CK2 inhibition-mediated effects with a particular emphasis on the combinatorial use of CK2 inhibitors as novel therapeutic strategies for treating both acute and chronic leukemia patients.Leukemia advance online publication, 24 October 2017},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_136,

title = {Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update.},

author = {Evangelisti C and Chiarini F and McCubrey JA and Martelli AM},

url = {https://www.mdpi.com/1422-0067/19/7/1878},

doi = {10.3390/ijms19071878},

year  = {2018},

date = {2018-01-26},

journal = {International journal of molecular sciences},

volume = {19},

number = {7},

pages = {pii: E1878},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood malignancy that arises from the clonal expansion of transformed T-cell precursors. Although T-ALL prognosis has significantly improved due to the development of intensive chemotherapeutic protocols, primary drug-resistant and relapsed patients still display a dismal outcome. In addition, lifelong irreversible late effects from conventional therapy are a growing problem for leukemia survivors. Therefore, novel targeted therapies are required to improve the prognosis of high-risk patients. The mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct multiprotein complexes, which are referred to as mTOR complex 1 (mTORC1) and mTORC2. These two complexes regulate a variety of physiological cellular processes including protein, lipid, and nucleotide synthesis, as well as autophagy in response to external cues. However, mTOR activity is frequently deregulated in cancer, where it plays a key oncogenetic role driving tumor cell proliferation, survival, metabolic transformation, and metastatic potential. Promising preclinical studies using mTOR inhibitors have demonstrated efficacy in many human cancer types, including T-ALL. Here, we highlight our current knowledge of mTOR signaling and inhibitors in T-ALL, with an emphasis on emerging evidence of the superior efficacy of combinations consisting of mTOR inhibitors and either traditional or targeted therapeutics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_204,

title = {PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines.},

author = {Ultimo S and Simioni C and Martelli AM and Zauli G and Evangelisti C and Celeghini C and McCubrey JA and Marisi G and Ulivi P and Capitani S and Neri LM},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=15542&pubmed-linkout=1},

doi = {10.18632/oncotarget.15542},

year  = {2017},

date = {2017-04-04},

journal = {Oncotarget},

volume = {8},

number = {14},

pages = {23213-23227},

abstract = {B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein.We studied the effects of anti Bcr-Abl drugs Imatinib, Nilotinib and GZD824 associated with PI3K isoform inhibitors. We used a panel of six compounds which specifically target PI3K isoforms including the pan-PI3K inhibitor ZSTK474, p110alpha BYL719 inhibitor and the dual p110gamma/p110delta inhibitor IPI145. The effects of single drugs and of several drug combinations were analyzed to assess cytotoxicity by MTS assays, apoptosis and autophagy by flow cytometry and Western blot, as well as the phosphorylation status of the pathway.ZSTK474, BYL719 and IPI145 administered in combination with imatinib, nilotinib and GZD824 for 48 h, decreased cell viability, induced apoptosis and autophagy in a marked synergistic manner.These findings suggest that selected PI3K isoform inhibitors used in combination with anti Bcr-Abl drugs may be an attractive novel therapeutic intervention in Ph+ B-ALL.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_320,

title = {Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting.},

author = {Chiarini F and Lonetti A and Evangelisti C and Buontempo F and Orsini E and Evangelisti C and Cappellini A and Neri LM and McCubrey JA and Martelli AM},

url = {http://www.sciencedirect.com/science/article/pii/S0167488915002931},

doi = {10.1016/j.bbamcr.2015.08.015. },

year  = {2016},

date = {2016-02-18},

journal = {Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research},

volume = {1863},

number = {3},

pages = {449-463},

abstract = {The bone marrow (BM) microenvironment regulates the properties of healthy hematopoietic stem cells (HSCs) localized in specific niches. Two distinct microenvironmental niches have been identified in the BM, the "osteoblastic (endosteal)" and "vascular" niches. Nevertheless, these niches provide sanctuaries where subsets of leukemic cells escape chemotherapy-induced death and acquire a drug-resistant phenotype. Moreover, it is emerging that leukemia cells are able to remodel the BM niches into malignant niches which better support neoplastic cell survival and proliferation. This review focuses on the cellular and molecular biology of microenvironment/leukemia interactions in acute lymphoblastic leukemia (ALL) of both B- and T-cell lineage. We shall also highlight the emerging role of exosomes/microvesicles as efficient messengers for cell-to-cell communication in leukemia settings. Studies on the interactions between the BM microenvironment and ALL cells have led to the discovery of potential therapeutic targets which include cytokines/chemokines and their receptors, adhesion molecules, signal transduction pathways, and hypoxia-related proteins. The complex interplays between leukemic cells and BM microenvironment components provide a rationale for innovative, molecularly targeted therapies, designed to improve ALL patient outcome. A better understanding of the contribution of the BM microenvironment to the process of leukemogenesis and leukemia persistence after initial remission, may provide new targets that will allow destruction of leukemia cells without adversely affecting healthy HSCs. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis,Inflammation, and Immune Surveillance. Guest Editors: Peter Ruvolo and Gregg L. Semenza. Copyright 2015 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_294,

title = {Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway.},

author = {Lonetti A and Cappellini A and Bertaina A and Locatelli F and Pession A and Buontempo F and Evangelisti C and Evangelisti C and Orsini E and Zambonin L and Neri LM and Martelli AM and Chiarini F},

url = {https://jhoonline.biomedcentral.com/articles/10.1186/s13045-016-0344-4},

doi = {10.1186/s13045-016-0344-4},

year  = {2016},

date = {2016-10-24},

journal = {Journal Of Hematology & Oncology },

volume = {9},

number = {1},

pages = {114},

abstract = {BACKGROUND: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine. METHODS: The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. RESULTS: Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. CONCLUSIONS: These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_274,

title = {Potential therapeutic effects of the mtor inhibitors for preventing ageing and progeria-related disorders.},

author = {Evangelisti C and Cenni V and Lattanzi G},

url = {http://onlinelibrary.wiley.com/doi/10.1111/bcp.12928/abstract;jsessionid=34B2DFDBFC206F2806B33262A44B1552.f03t02},

doi = {10.1111/bcp.12928},

year  = {2016},

date = {2016-11-30},

journal = {British Journal of Clinical Pharmacology (Literature Review)},

volume = {82},

number = {5},

pages = {1229-1244},

abstract = {The mammalian target of rapamycin (mTOR) pathway is an highly conserved signal transduction axis involved in many cellular processes such as cell growth, survival, transcription, translation, apoptosis, metabolism, motility and autophagy. Recently, such signaling pathway has come to the attention of the scientific community due to the unexpected finding that inhibition of mTOR by rapamycin, an antibiotic with immunosuppressant and chemotherapeutic properties, extends life-span in diverse animal models. Moreover, rapamycin has been reported to rescue the cellular phenotype in a progeroid syndrome that recapitulates most of the traits of physiological ageing, the Hutchinson-Gilford Progeria (HGPS). The promising perspectives raised by those results warrant a better understanding of mTOR signaling and of potential applications of mTOR inhibitors to counteract ageing-associated diseases and increase longevity. This review is focused on these issues. This article is protected by copyright. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_255,

title = {Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-κB.},

author = {Buontempo F and Orsini E and Lonetti A and Cappellini A and Chiarini F and Evangelisti C and Evangelisti C and Melchionda F and Pession A and Bertaina A and Locatelli F and Bertacchini J and Neri LM and McCubrey JA and Martelli AM},

url = {http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=6361&pubmed-linkout=1},

doi = {10.18632/oncotarget.6361},

year  = {2016},

date = {2016-01-22},

journal = {Oncotarget},

volume = {7},

number = {2},

pages = {1323-1340},

abstract = {The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_275,

title = {Therapeutic potential of targeting sphingosine kinases and sphingosine 1-phosphate in hematological malignancies.},

author = {Evangelisti C and Evangelisti C and Buontempo F and Lonetti A and Orsini E and Chiarini F and Barata JT and Pyne S and Pyne NJ and Martelli AM},

editor = {Ardizzoni A},

doi = {10.1038/leu.2016.208},

year  = {2016},

date = {2016-11-17},

journal = {Leukemia},

volume = {30},

number = {11},

pages = {2142-2151},

abstract = {Sphingolipids such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P), are bioactive molecules that have important functions in a variety of cellular processes, which include proliferation, survival, differentiation and cellular responses to stress. Sphingolipids have a major impact on determination of the cell fate by contributing to either cell survival or death. While ceramide and sphingosine are usually considered to induce cell death, S1P promotes survival of cells. Sphingosine kinases (SPHKs) are the enzymes that catalyze the conversion of sphingosine to S1P. There are two isoforms, SPHK1 and SPHK2, which are encoded by different genes. SPHK1 has recently been implicated in contributing to cell transformation, tumor angiogenesis, and metastatic spread, as well as cancer cell multidrug-resistance. More recent findings suggest that SPHK2 also has a role in cancer progression. This review is an overview of our understanding of the role of SPHKs and S1P in hematopoietic malignancies and provides information on the current status of SPHK inhibitors with respect to their therapeutic potential in the treatment of hematological cancers.Leukemia accepted article preview online, 27 July 2016. doi:10.1038/leu.2016.208.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_339,

title = {Autophagy in acute leukemias: A double-edged sword with important therapeutic implications},

author = {Evangelisti C and Evangelisti C and Chiarini F and Lonetti A and Buontempo F and Neri LM and McCubrey JA and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0167488914003486?via%3Dihub},

doi = {10.1016/j.bbamcr.2014.09.023},

year  = {2015},

date = {2015-02-18},

journal = {Biochimica et Biophysica Acta (BBA) - Molecular Cell Research},

volume = {1853},

number = {1},

pages = {14-26},

abstract = {Macroautophagy, usually referred to as autophagy, is a degradative pathway wherein cytoplasmatic components such as aggregated/misfolded proteins and organelles are engulfed within double-membrane vesicles (autophagosomes) and then delivered to lysosomes for degradation. Autophagy plays an important role in the regulation of numerous physiological functions, including hematopoiesis, through elimination of aggregated/misfolded proteins, and damaged/superfluous organelles. The catabolic products of autophagy (amino acids, fatty acids, nucleotides) are released into the cytosol from autophagolysosomes and recycled into bio-energetic pathways. Therefore, autophagy allows cells to survive starvation and other unfavorable conditions, including hypoxia, heat shock, and microbial pathogens. Nevertheless, depending upon the cell context and functional status, autophagy can also serve as a death mechanism. The cohort of proteins that constitute the autophagy machinery function in a complex, multistep biochemical pathway which has been partially identified over the past decade. Dysregulation of autophagy may contribute to the development of several disorders, including acute leukemias. In this kind of hematologic malignancies, autophagy can either act as a chemo-resistance mechanism or have tumor suppressive functions, depending on the context. Therefore, strategies exploiting autophagy, either for activating or inhibiting it, could find a broad application for innovative treatment of acute leukemias and could significantly contribute to improved clinical outcomes. These aspects are discussed here after a brief introduction to the autophagic molecular machinery and its roles in hematopoiesis.Copyright  2014 Elsevier B.V. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_351,

title = {Current treatment strategies for inhibiting mTOR in cancer},

author = {Chiarini F and Evangelisti C and McCubrey JA and Martelli AM},

url = {https://www.sciencedirect.com/science/article/pii/S0165614714001953?via%3Dihub},

doi = {10.1016/j.tips.2014.11.004},

year  = {2015},

date = {2015-02-11},

journal = {Trends in Pharmacological Sciences},

volume = {36},

number = {2},

abstract = {Mammalian target of rapamycin (mTOR) is a Ser/Thr kinase that regulates a wide range of functions, including cell growth, proliferation, survival, autophagy, metabolism, and cytoskeletal organization. mTOR activity is dysregulated in several human disorders, including cancer. The crucial role of mTOR in cancer cell biology has stimulated interest in mTOR inhibitors, placing mTOR on the radar of the pharmaceutical industry. Several mTOR inhibitors have already undergone clinical trials for treating tumors, without great success, although mTOR inhibitors are approved for the treatment of some types of cancer, including advanced renal cell carcinoma. However, the role of mTOR inhibitors in cancer treatment continues to evolve as new compounds are continuously being disclosed. Here we review the three classes of mTOR inhibitors currently available for treating cancer patients. Moreover, we highlight efforts to identify markers of resistance and sensitivity to mTOR inhibition that could prove useful in the emerging field of personalized medicine.Copyright 2014 Elsevier Ltd. All rights reserved.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_381,

title = {Modulation of TGFbeta 2 levels by lamin A in U2-OS osteoblast-like cells: understanding the osteolytic process triggered by altered lamins.},

author = {Evangelisti C and Bernasconi P and Cavalcante P and Cappelletti C and D'Apice MR and Sbraccia P and Novelli G and Prencipe S and Lemma S and Baldini N and Avnet S and Squarzoni S and Martelli AM and Lattanzi G},

url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=3232&pubmed-linkout=1},

year  = {2015},

date = {2015-04-10},

journal = {Oncotarget},

volume = {6},

number = {10},

pages = {7424-7437},

abstract = {Transforming growth factor beta (TGFbeta) plays an essential role in bone homeostasis and deregulation of TGFbeta occurs in bone pathologies. Patients affected by Mandibuloacral Dysplasia (MADA), a progeroid disease linked to LMNA mutations, suffer from an osteolytic process. Our previous work showed that MADA osteoblasts secrete excess amount of TGFbeta 2, which in turn elicits differentiation of human blood precursors into osteoclasts. Here, we sought to determine how altered lamin A affects TGFbeta signaling. Our results show that wild-type lamin A negatively modulates TGFbeta 2 levels in osteoblast-like U2-OS cells, while the R527H mutated prelamin A as well as farnesylated prelamin A do not, ultimately leading to increased secretion of TGFbeta 2. TGFbeta 2 in turn, triggers the Akt/mTOR pathway and upregulates osteoprotegerin and cathepsin K. TGFbeta 2 neutralization rescues Akt/mTOR activation and the downstream transcriptional effects, an effect also obtained by statins or RAD001 treatment. Our results unravel an unexpected role of lamin A in TGFbeta 2 regulation and indicate rapamycin analogs and neutralizing antibodies to TGFbeta 2 as new potential therapeutic tools for MADA.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{%a1:%Y_393,

title = {PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors.},

author = {Lonetti A and Cappellini A and Spartà AM and Chiarini F and Buontempo F and Evangelisti C and Evangelisti C and Orsini E and McCubrey JA and Martelli AM},

url = {https://www.fasebj.org/doi/full/10.1096/fj.14-259051?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&},

year  = {2015},

date = {2015-04-15},

journal = {Oncotarget},

volume = {6},

number = {12},

pages = {10399-10414},

abstract = {Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110γ/δ inhibition. Intriguingly, the dual p110γ/δ inhibitor IPI-145 was effective in Loucy cells, which are representative of early T-precursor (ETP)-ALL, a T-ALL subtype associated with a poor outcome. PTEN gene deletion did not confer a peculiar reliance of T-ALL cells on PI3K activity for their proliferation/survival, as PTEN was inactivated in PTEN non deleted cells, due to posttranslational mechanisms. PI3K pan-inhibition suppressed Akt activation and induced caspase-independent apoptosis. We further demonstrated that in some T-ALL cell lines, autophagy could exert a protective role against PI3K inhibition. Our findings strongly support clinical application of class I PI3K pan-inhibitors in T-ALL treatment, with the possible exception of ETP-ALL cases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}