2021
|
Chiodi I; Perini C; Berardi D; Mondello C Asparagine sustains cellular proliferation and c‑Myc expression in glutamine‑starved cancer cells Journal Article In: Oncology reports, vol. 45, no 6, pp. 96, 2021. @article{%a1:%Ybv,
title = {Asparagine sustains cellular proliferation and c‑Myc expression in glutamine‑starved cancer cells},
author = {Chiodi I and Perini C and Berardi D and Mondello C},
url = {https://www.spandidos-publications.com/or/45/6/96},
doi = {10.3892/or.2021.8047},
year = {2021},
date = {2021-08-30},
journal = {Oncology reports},
volume = {45},
number = {6},
pages = {96},
abstract = {During tumorigenesis, oncogene activation and metabolism rewiring are interconnected. Activated c‑Myc upregulates several genes involved in glutamine metabolism, making cancer cells dependent on high levels of this amino acid to survive and proliferate. After studying the response to glutamine deprivation in cancer cells, it was found that glutamine starvation not only blocked cellular proliferation, but also altered c‑Myc protein expression, leading to a reduction in the levels of the canonical c‑Myc isoform and an increase in the expression of c‑Myc 1, a c‑Myc isoform translated from an in‑frame 5' CUG codon. In an attempt to identify nutrients able to counteract glutamine deprivation effects, it was shown that, in the absence of glutamine, asparagine permitted cell survival and proliferation, and maintained c‑Myc expression as in glutamine‑fed cells, with high levels of canonical c‑Myc and c‑Myc 1 almost undetectable. In asparagine‑fed cells, global protein translation was higher than in glutamine‑starved cells, and there was an increase in the levels of glutamine synthetase (GS), whose activity was essential for cellular viability and proliferation. In glutamine‑starved asparagine‑fed cells, the inhibition of c‑Myc activity led to a decrease in global protein translation and GS synthesis, suggesting an association between c‑Myc expression, GS levels and cellular proliferation, mediated by asparagine when exogenous glutamine is absent.},
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During tumorigenesis, oncogene activation and metabolism rewiring are interconnected. Activated c‑Myc upregulates several genes involved in glutamine metabolism, making cancer cells dependent on high levels of this amino acid to survive and proliferate. After studying the response to glutamine deprivation in cancer cells, it was found that glutamine starvation not only blocked cellular proliferation, but also altered c‑Myc protein expression, leading to a reduction in the levels of the canonical c‑Myc isoform and an increase in the expression of c‑Myc 1, a c‑Myc isoform translated from an in‑frame 5' CUG codon. In an attempt to identify nutrients able to counteract glutamine deprivation effects, it was shown that, in the absence of glutamine, asparagine permitted cell survival and proliferation, and maintained c‑Myc expression as in glutamine‑fed cells, with high levels of canonical c‑Myc and c‑Myc 1 almost undetectable. In asparagine‑fed cells, global protein translation was higher than in glutamine‑starved cells, and there was an increase in the levels of glutamine synthetase (GS), whose activity was essential for cellular viability and proliferation. In glutamine‑starved asparagine‑fed cells, the inhibition of c‑Myc activity led to a decrease in global protein translation and GS synthesis, suggesting an association between c‑Myc expression, GS levels and cellular proliferation, mediated by asparagine when exogenous glutamine is absent. |
2020
|
Chiodi I; Mondello C Life Style Factors, Tumor Cell Plasticity and Cancer Stem Cells Journal Article In: Mutation Research - Reviews in Mutation Research, vol. 784, pp. 108308, 2020. @article{%a1:%Y_438,
title = {Life Style Factors, Tumor Cell Plasticity and Cancer Stem Cells},
author = {Chiodi I and Mondello C},
url = {https://www.sciencedirect.com/science/article/pii/S1383574220300284?via%3Dihub},
doi = {10.1016/j.mrrev.2020.108308},
year = {2020},
date = {2020-01-01},
journal = {Mutation Research - Reviews in Mutation Research},
volume = {784},
pages = {108308},
abstract = {Cancers are heterogeneous tissues and a layer of heterogeneity is determined by the presence of cells showing stemness traits, known as cancer stem cells (CSCs). Evidence indicates that CSCs are important players in tumor development, progression and relapse. Oncogenic transformation of normal stem cells can give rise to CSCs, but CSCs can also originate from de-differentiation of bulk tumor cells. Thus, factors promoting the increase of normal stem cell pools or stimulating the acquisition of stemness features by tumor cells can have serious consequences on cancer origin and progression. In this review, we will first give an overview of the CSC model of cancer development and we will then discuss the role of life style factors, such as high caloric diet, alcohol drinking and smoking, on the widening of stem cell pools and the induction of CSC features in tumors. Finally, we will discuss some healthy life style factors that can help to prevent cancer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
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Cancers are heterogeneous tissues and a layer of heterogeneity is determined by the presence of cells showing stemness traits, known as cancer stem cells (CSCs). Evidence indicates that CSCs are important players in tumor development, progression and relapse. Oncogenic transformation of normal stem cells can give rise to CSCs, but CSCs can also originate from de-differentiation of bulk tumor cells. Thus, factors promoting the increase of normal stem cell pools or stimulating the acquisition of stemness features by tumor cells can have serious consequences on cancer origin and progression. In this review, we will first give an overview of the CSC model of cancer development and we will then discuss the role of life style factors, such as high caloric diet, alcohol drinking and smoking, on the widening of stem cell pools and the induction of CSC features in tumors. Finally, we will discuss some healthy life style factors that can help to prevent cancer. |
2019
|
Chiodi I; Picco G; Martino C; Mondello C Cellular response to glutamine and/or glucose deprivation in in vitro transformed human fibroblasts. Journal Article In: Oncology reports, vol. 41, no 6, pp. 3555-3564, 2019. @article{%a1:%Y%v,
title = {Cellular response to glutamine and/or glucose deprivation in in vitro transformed human fibroblasts.},
author = {Chiodi I and Picco G and Martino C and Mondello C},
url = {https://www.spandidos-publications.com/or/41/6/3555},
doi = {10.3892/or.2019.7125},
year = {2019},
date = {2019-02-22},
journal = {Oncology reports},
volume = {41},
number = {6},
pages = {3555-3564},
abstract = {Neoplastic transformation is characterized by metabolic rewiring to sustain the elevated biosynthetic demands of highly proliferative cancer cells. To obtain the precursors for macromolecule biosynthesis, cancer cells avidly uptake and metabolize glucose and glutamine. Thus, targeting the availability or metabolism of these nutrients is an attractive anticancer therapeutic strategy. To improve our knowledge concerning how cancer cells respond to nutrient withdrawal, the response to glutamine and/or glucose starvation was studied in human in vitro transformed fibroblasts, deeply characterized at the cellular and molecular level. Concomitant starvation of both nutrients led to rapid loss of cellular adhesion (~16 h after starvation), followed by cell death. Deprivation of glucose alone had the same effect, although at a later time (~48 h after starvation), suggesting that glucose plays a key role in enabling cell attachment to the extracellular matrix. Glutamine deprivation did not induce rapid cell death, but caused a prolonged arrest of cellular proliferation; the cells started dying only 96 h after starvation. Before massive cell death occurred, the effects of all the starvation conditions were reversible. Autophagy activation was observed in cells incubated in the absence of glucose for more than 48 h, while autophagy was not detected under the other starvation conditions. Markers of apoptotic cell death, such as caspase 3, caspase 9 and poly(ADP‑ribose) polymerase 1 (PARP‑1) proteolytic fragments, were not observed under any growth condition. Glucose and/or glutamine deprivation caused very rapid PARP‑1 activation, with marked PARP‑1 (poly‑ADP) ribosylation and protein (poly‑ADP) ribosylation. This activation was not due to starvation‑induced DNA double‑strand breaks, which appeared at the late stages of deprivation, when most cells died. Collectively, these results highlight a broad range of consequences of glucose and glutamine starvation, which may be taken into account when nutrient availability is used as a target for anticancer therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
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Neoplastic transformation is characterized by metabolic rewiring to sustain the elevated biosynthetic demands of highly proliferative cancer cells. To obtain the precursors for macromolecule biosynthesis, cancer cells avidly uptake and metabolize glucose and glutamine. Thus, targeting the availability or metabolism of these nutrients is an attractive anticancer therapeutic strategy. To improve our knowledge concerning how cancer cells respond to nutrient withdrawal, the response to glutamine and/or glucose starvation was studied in human in vitro transformed fibroblasts, deeply characterized at the cellular and molecular level. Concomitant starvation of both nutrients led to rapid loss of cellular adhesion (~16 h after starvation), followed by cell death. Deprivation of glucose alone had the same effect, although at a later time (~48 h after starvation), suggesting that glucose plays a key role in enabling cell attachment to the extracellular matrix. Glutamine deprivation did not induce rapid cell death, but caused a prolonged arrest of cellular proliferation; the cells started dying only 96 h after starvation. Before massive cell death occurred, the effects of all the starvation conditions were reversible. Autophagy activation was observed in cells incubated in the absence of glucose for more than 48 h, while autophagy was not detected under the other starvation conditions. Markers of apoptotic cell death, such as caspase 3, caspase 9 and poly(ADP‑ribose) polymerase 1 (PARP‑1) proteolytic fragments, were not observed under any growth condition. Glucose and/or glutamine deprivation caused very rapid PARP‑1 activation, with marked PARP‑1 (poly‑ADP) ribosylation and protein (poly‑ADP) ribosylation. This activation was not due to starvation‑induced DNA double‑strand breaks, which appeared at the late stages of deprivation, when most cells died. Collectively, these results highlight a broad range of consequences of glucose and glutamine starvation, which may be taken into account when nutrient availability is used as a target for anticancer therapies. |
2018
|
Bono B; Ostano P; Peritore M; Gregnanin I; Belgiovine C; Liguori M; Allavena P; Chiorino G; Chiodi I; Mondello C Cells with stemness features are generated from in vitro transformed human fibroblasts. Journal Article In: Scientific Reports, vol. 8, no 1, pp. 13838, 2018. @article{%a1:%Y_323,
title = {Cells with stemness features are generated from in vitro transformed human fibroblasts.},
author = {Bono B and Ostano P and Peritore M and Gregnanin I and Belgiovine C and Liguori M and Allavena P and Chiorino G and Chiodi I and Mondello C},
url = {https://www.nature.com/articles/s41598-018-32197-5},
doi = {10.1038/s41598-018-32197-5},
year = {2018},
date = {2018-02-15},
journal = {Scientific Reports},
volume = {8},
number = {1},
pages = {13838},
abstract = {Cancer stem cells (CSCs) have been involved in the maintenance, progression and relapse of several tumors, but their origin is still elusive. Here, in vitro transformed human fibroblasts (cen3tel cells) and the tumorsphere assay were used to search for and possibly characterize CSCs in transformed somatic cells. Cen3tel cells formed spheres showing self-renewal capacity and Sox2 overexpression, suggesting that they contained a subset of cells with CSC-like features. Sphere cells displayed deregulation of a c-MYC/miR-34a circuitry, likely associated with cell protection from apoptosis. Gene expression profiles of sphere cells revealed an extensive transcriptional reprogramming. Genes up-regulated in tumorspheres identified processes related to tumorigenesis and stemness, as cholesterol biosynthesis, apoptosis suppression, interferon and cytokine mediated signalling pathways. Sphere cells engrafted into NSG mice more rapidly than adherent cells, but both cell populations were tumorigenic. These results indicate that, during transformation, human somatic cells can acquire CSC properties, confirming the high plasticity of tumor cells. However, CSC-like cells are not the only tumorigenic population in transformed cells, indicating that the CSC phenotype and tumorigenicity can be uncoupled.},
keywords = {},
pubstate = {published},
tppubtype = {article}
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Cancer stem cells (CSCs) have been involved in the maintenance, progression and relapse of several tumors, but their origin is still elusive. Here, in vitro transformed human fibroblasts (cen3tel cells) and the tumorsphere assay were used to search for and possibly characterize CSCs in transformed somatic cells. Cen3tel cells formed spheres showing self-renewal capacity and Sox2 overexpression, suggesting that they contained a subset of cells with CSC-like features. Sphere cells displayed deregulation of a c-MYC/miR-34a circuitry, likely associated with cell protection from apoptosis. Gene expression profiles of sphere cells revealed an extensive transcriptional reprogramming. Genes up-regulated in tumorspheres identified processes related to tumorigenesis and stemness, as cholesterol biosynthesis, apoptosis suppression, interferon and cytokine mediated signalling pathways. Sphere cells engrafted into NSG mice more rapidly than adherent cells, but both cell populations were tumorigenic. These results indicate that, during transformation, human somatic cells can acquire CSC properties, confirming the high plasticity of tumor cells. However, CSC-like cells are not the only tumorigenic population in transformed cells, indicating that the CSC phenotype and tumorigenicity can be uncoupled. |
2016
|
Yang T; Bragheri F; Nava G; Chiodi I; Mondello C; Osellame R; Berg-Sørensen K; Cristiani I; Minzioni P A comprehensive strategy for the analysis of acoustic compressibility and optical deformability on single cells. Journal Article In: Scientific Reports, vol. 6, pp. 23946, 2016. @article{%a1:%Y_319,
title = {A comprehensive strategy for the analysis of acoustic compressibility and optical deformability on single cells.},
author = {Yang T and Bragheri F and Nava G and Chiodi I and Mondello C and Osellame R and Berg-Sørensen K and Cristiani I and Minzioni P},
url = {http://www.nature.com/articles/srep23946},
doi = {10.1038/srep23946},
year = {2016},
date = {2016-04-20},
journal = {Scientific Reports},
volume = {6},
pages = {23946},
abstract = {We realized an integrated microfluidic chip that allows measuring both optical deformability and acoustic compressibility on single cells, by optical stretching and acoustophoresis experiments respectively. Additionally, we propose a measurement protocol that allows evaluating the experimental apparatus parameters before performing the cell-characterization experiments, including a non-destructive method to characterize the optical force distribution inside the microchannel. The chip was used to study important cell-mechanics parameters in two human breast cancer cell lines, MCF7 and MDA-MB231. Results indicate that MDA-MB231 has both higher acoustic compressibility and higher optical deformability than MCF7, but statistical analysis shows that optical deformability and acoustic compressibility are not correlated parameters. This result suggests the possibility to use them to analyze the response of different cellular structures. We also demonstrate that it is possible to perform both measurements on a single cell, and that the order of the two experiments does not affect the retrieved values.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We realized an integrated microfluidic chip that allows measuring both optical deformability and acoustic compressibility on single cells, by optical stretching and acoustophoresis experiments respectively. Additionally, we propose a measurement protocol that allows evaluating the experimental apparatus parameters before performing the cell-characterization experiments, including a non-destructive method to characterize the optical force distribution inside the microchannel. The chip was used to study important cell-mechanics parameters in two human breast cancer cell lines, MCF7 and MDA-MB231. Results indicate that MDA-MB231 has both higher acoustic compressibility and higher optical deformability than MCF7, but statistical analysis shows that optical deformability and acoustic compressibility are not correlated parameters. This result suggests the possibility to use them to analyze the response of different cellular structures. We also demonstrate that it is possible to perform both measurements on a single cell, and that the order of the two experiments does not affect the retrieved values. |
Belgiovine C; Chiesa G; Chiodi I; Frapolli R; Bonezzi K; Taraboletti G; D'Incalci M; Mondello C Snail levels control the migration mechanism of mesenchymal tumor cells. Journal Article In: Oncology Letters, vol. 12, no 1, pp. 767-771, 2016. @article{%a1:%Y_252,
title = {Snail levels control the migration mechanism of mesenchymal tumor cells.},
author = {Belgiovine C and Chiesa G and Chiodi I and Frapolli R and Bonezzi K and Taraboletti G and D'Incalci M and Mondello C},
url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907273/},
doi = {10.3892/ol.2016.4642},
year = {2016},
date = {2016-03-16},
journal = {Oncology Letters},
volume = {12},
number = {1},
pages = {767-771},
abstract = {Cancer cells use two major types of movement: Mesenchymal, which is typical of cells of mesenchymal origin and depends on matrix metalloproteinase (MMP) activity, and amoeboid, which is characteristic of cells with a rounded shape and relies on the activity of Rho-associated kinase (ROCK). The present authors previously demonstrated that, during neoplastic transformation, telomerase-immortalized human fibroblasts (cen3tel cells) acquired a ROCK-dependent/MMP independent mechanism of invasion, mediated by the downregulation of the ROCK cellular inhibitor Round (Rnd)3/RhoE. In the present study, cen3tel transformation was also demonstrated to be paralleled by downregulation of Snail, a major determinant of the mesenchymal movement. To test whether Snail levels could determine the type of movement adopted by mesenchymal tumor cells, Snail was ectopically expressed in tumorigenic cells. It was observed that ectopic Snail did not increase the levels of typical mesenchymal markers, but induced cells to adopt an MMP-dependent mechanism of invasion. In cells expressing ectopic Snail, invasion became sensitive to the MMP inhibitor Ro 28-2653 and insensitive to the ROCK inhibitor Y27632, suggesting that, once induced by Snail, the mesenchymal movement prevails over the amoeboid one. Snail-expressing cells had a more aggressive behavior in vivo, and exhibited increased tumor growth rate and metastatic ability. These results confirm the high plasticity of cancer cells, which can adopt different types of movement in response to changes in the expression of specific genes. Furthermore, the present findings indicate that Rnd3 and Snail are possible regulators of the type of invasion mechanism adopted by mesenchymal tumor cells.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cancer cells use two major types of movement: Mesenchymal, which is typical of cells of mesenchymal origin and depends on matrix metalloproteinase (MMP) activity, and amoeboid, which is characteristic of cells with a rounded shape and relies on the activity of Rho-associated kinase (ROCK). The present authors previously demonstrated that, during neoplastic transformation, telomerase-immortalized human fibroblasts (cen3tel cells) acquired a ROCK-dependent/MMP independent mechanism of invasion, mediated by the downregulation of the ROCK cellular inhibitor Round (Rnd)3/RhoE. In the present study, cen3tel transformation was also demonstrated to be paralleled by downregulation of Snail, a major determinant of the mesenchymal movement. To test whether Snail levels could determine the type of movement adopted by mesenchymal tumor cells, Snail was ectopically expressed in tumorigenic cells. It was observed that ectopic Snail did not increase the levels of typical mesenchymal markers, but induced cells to adopt an MMP-dependent mechanism of invasion. In cells expressing ectopic Snail, invasion became sensitive to the MMP inhibitor Ro 28-2653 and insensitive to the ROCK inhibitor Y27632, suggesting that, once induced by Snail, the mesenchymal movement prevails over the amoeboid one. Snail-expressing cells had a more aggressive behavior in vivo, and exhibited increased tumor growth rate and metastatic ability. These results confirm the high plasticity of cancer cells, which can adopt different types of movement in response to changes in the expression of specific genes. Furthermore, the present findings indicate that Rnd3 and Snail are possible regulators of the type of invasion mechanism adopted by mesenchymal tumor cells. |
Chiodi I; Mondello C Telomere and telomerase stability in human diseases and cancer. Journal Article In: Frontiers In Bioscience, vol. 21, pp. 203-224, 2016. @article{%a1:%Y_261,
title = {Telomere and telomerase stability in human diseases and cancer.},
author = {Chiodi I and Mondello C},
year = {2016},
date = {2016-03-11},
journal = {Frontiers In Bioscience},
volume = {21},
pages = {203-224},
abstract = {Telomeres are the nucleoprotein structures at the end of linear eukaryotic chromosomes required for genome stability. Telomerase is the specialized enzyme deputed to their elongation. Maintenance of a proper telomere structure, an accurate regulation of telomerase biogenesis and activity, as well as a correct telomere-telomerase interaction and a faithful telomeric DNA replication are all processes that a cell has to precisely control to safeguard its functionality. Here, we review key factors that play a role in the development of these processes and their relationship with human health.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Telomeres are the nucleoprotein structures at the end of linear eukaryotic chromosomes required for genome stability. Telomerase is the specialized enzyme deputed to their elongation. Maintenance of a proper telomere structure, an accurate regulation of telomerase biogenesis and activity, as well as a correct telomere-telomerase interaction and a faithful telomeric DNA replication are all processes that a cell has to precisely control to safeguard its functionality. Here, we review key factors that play a role in the development of these processes and their relationship with human health. |
2015
|
Martinez Vazquez R; Nava G; Veglione M; Yang T; Bragheri F; Minzioni P; Bianchi E; Di Tano M; Chiodi I; Osellame R; Mondello C; Cristiani I An optofluidic constriction chip for monitoring metastatic potential and drug response of cancer cells. Journal Article In: Integrative Biology, vol. 7, no 4, pp. 477-484, 2015. @article{%a1:%Y_333,
title = {An optofluidic constriction chip for monitoring metastatic potential and drug response of cancer cells.},
author = {{Martinez Vazquez R} and Nava G and Veglione M and Yang T and Bragheri F and Minzioni P and Bianchi E and Di Tano M and Chiodi I and Osellame R and Mondello C and Cristiani I},
url = {https://academic.oup.com/ib/article-abstract/7/4/477/5199149?redirectedFrom=fulltext},
doi = {10.1039/c5ib00023h},
year = {2015},
date = {2015-02-11},
journal = {Integrative Biology},
volume = {7},
number = {4},
pages = {477-484},
abstract = {Cellular mechanical properties constitute good markers to characterize tumor cells, to study cell population heterogeneity and to highlight the effect of drug treatments. In this work, we describe the fabrication and validation of an integrated optofluidic chip capable of analyzing cellular deformability on the basis of the pressure gradient needed to push a cell through a narrow constriction. We demonstrate the ability of the chip to discriminate between tumorigenic and metastatic breast cancer cells (MCF7 and MDA-MB231) and between human melanoma cells with different metastatic potential (A375P and A375MC2). Moreover, we show that this chip allows highlighting the effect of drugs interfering with microtubule organization (paclitaxel, combretastatin A-4 and nocodazole) on cancer cells, which leads to changes in the pressure-gradient required to push cells through the constriction. Our single-cell microfluidic device for mechanical evaluation is compact and easy to use, allowing for an extensive use in different laboratory environments.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cellular mechanical properties constitute good markers to characterize tumor cells, to study cell population heterogeneity and to highlight the effect of drug treatments. In this work, we describe the fabrication and validation of an integrated optofluidic chip capable of analyzing cellular deformability on the basis of the pressure gradient needed to push a cell through a narrow constriction. We demonstrate the ability of the chip to discriminate between tumorigenic and metastatic breast cancer cells (MCF7 and MDA-MB231) and between human melanoma cells with different metastatic potential (A375P and A375MC2). Moreover, we show that this chip allows highlighting the effect of drugs interfering with microtubule organization (paclitaxel, combretastatin A-4 and nocodazole) on cancer cells, which leads to changes in the pressure-gradient required to push cells through the constriction. Our single-cell microfluidic device for mechanical evaluation is compact and easy to use, allowing for an extensive use in different laboratory environments. |
