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Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling

Systems Biology holds that complex cellular functions are generated as system-level properties endowed with robustness, each involving large networks of molecular determinants, generally identified by “omics” analyses. In this paper we describe four basic cancer cell properties that can easily be in...

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Autores principales: Alberghina, Lilia, Gaglio, Daniela, Gelfi, Cecilia, Moresco, Rosa M., Mauri, Giancarlo, Bertolazzi, Paola, Messa, Cristina, Gilardi, Maria C., Chiaradonna, Ferdinando, Vanoni, Marco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440026/
https://www.ncbi.nlm.nih.gov/pubmed/22988443
http://dx.doi.org/10.3389/fphys.2012.00362
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author Alberghina, Lilia
Gaglio, Daniela
Gelfi, Cecilia
Moresco, Rosa M.
Mauri, Giancarlo
Bertolazzi, Paola
Messa, Cristina
Gilardi, Maria C.
Chiaradonna, Ferdinando
Vanoni, Marco
author_facet Alberghina, Lilia
Gaglio, Daniela
Gelfi, Cecilia
Moresco, Rosa M.
Mauri, Giancarlo
Bertolazzi, Paola
Messa, Cristina
Gilardi, Maria C.
Chiaradonna, Ferdinando
Vanoni, Marco
author_sort Alberghina, Lilia
collection PubMed
description Systems Biology holds that complex cellular functions are generated as system-level properties endowed with robustness, each involving large networks of molecular determinants, generally identified by “omics” analyses. In this paper we describe four basic cancer cell properties that can easily be investigated in vitro: enhanced proliferation, evasion from apoptosis, genomic instability, and inability to undergo oncogene-induced senescence. Focusing our analysis on a K-ras dependent transformation system, we show that enhanced proliferation and evasion from apoptosis are closely linked, and present findings that indicate how a large metabolic remodeling sustains the enhanced growth ability. Network analysis of transcriptional profiling gives the first indication on this remodeling, further supported by biochemical investigations and metabolic flux analysis (MFA). Enhanced glycolysis, down-regulation of TCA cycle, decoupling of glucose and glutamine utilization, with increased reductive carboxylation of glutamine, so to yield a sustained production of growth building blocks and glutathione, are the hallmarks of enhanced proliferation. Low glucose availability specifically induces cell death in K-ras transformed cells, while PKA activation reverts this effect, possibly through at least two mitochondrial targets. The central role of mitochondria in determining the two investigated cancer cell properties is finally discussed. Taken together the findings reported herein indicate that a system-level property is sustained by a cascade of interconnected biochemical pathways that behave differently in normal and in transformed cells.
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spelling pubmed-34400262012-09-17 Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling Alberghina, Lilia Gaglio, Daniela Gelfi, Cecilia Moresco, Rosa M. Mauri, Giancarlo Bertolazzi, Paola Messa, Cristina Gilardi, Maria C. Chiaradonna, Ferdinando Vanoni, Marco Front Physiol Physiology Systems Biology holds that complex cellular functions are generated as system-level properties endowed with robustness, each involving large networks of molecular determinants, generally identified by “omics” analyses. In this paper we describe four basic cancer cell properties that can easily be investigated in vitro: enhanced proliferation, evasion from apoptosis, genomic instability, and inability to undergo oncogene-induced senescence. Focusing our analysis on a K-ras dependent transformation system, we show that enhanced proliferation and evasion from apoptosis are closely linked, and present findings that indicate how a large metabolic remodeling sustains the enhanced growth ability. Network analysis of transcriptional profiling gives the first indication on this remodeling, further supported by biochemical investigations and metabolic flux analysis (MFA). Enhanced glycolysis, down-regulation of TCA cycle, decoupling of glucose and glutamine utilization, with increased reductive carboxylation of glutamine, so to yield a sustained production of growth building blocks and glutathione, are the hallmarks of enhanced proliferation. Low glucose availability specifically induces cell death in K-ras transformed cells, while PKA activation reverts this effect, possibly through at least two mitochondrial targets. The central role of mitochondria in determining the two investigated cancer cell properties is finally discussed. Taken together the findings reported herein indicate that a system-level property is sustained by a cascade of interconnected biochemical pathways that behave differently in normal and in transformed cells. Frontiers Media S.A. 2012-09-12 /pmc/articles/PMC3440026/ /pubmed/22988443 http://dx.doi.org/10.3389/fphys.2012.00362 Text en Copyright © 2012 Alberghina, Gaglio, Gelfi, Moresco, Mauri, Bertolazzi, Messa, Gilardi, Chiaradonna and Vanoni. http://www.frontiersin.org/licenseagreement This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
spellingShingle Physiology
Alberghina, Lilia
Gaglio, Daniela
Gelfi, Cecilia
Moresco, Rosa M.
Mauri, Giancarlo
Bertolazzi, Paola
Messa, Cristina
Gilardi, Maria C.
Chiaradonna, Ferdinando
Vanoni, Marco
Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling
title Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling
title_full Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling
title_fullStr Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling
title_full_unstemmed Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling
title_short Cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling
title_sort cancer cell growth and survival as a system-level property sustained by enhanced glycolysis and mitochondrial metabolic remodeling
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440026/
https://www.ncbi.nlm.nih.gov/pubmed/22988443
http://dx.doi.org/10.3389/fphys.2012.00362
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