The bioenergetic signature of cancer

2 páginas.-- Presentación oral al 16º International Charles Heidelberger Symposium on Cancer Research celebrado en Coimbra (Portugal) del 26 al 28 de Septiembre de 2010.Peer reviewe

La mitocondria: un nuevo paradigma en oncología

La revitalización del metabolismo energético en la biología del cáncer ha experimentado un fuerte impulso en los últimos años habiéndose establecido una estrecha relación de éste con los genes clásicos del cáncer. Sin embargo, el papel que desempeña la actividad bioenergética de la mitocondria en la progresión de la enfermedad es tema actual de debate. La reprogramación metabólica de las células cancerígenas es una característica fenotípica necesaria para la proliferación y supervivencia celular. Estudios recientes han demostrado a nivel transcriptómico, proteómico y funcional que la progresión del cáncer requiere, inevitablemente, la selección de las células cancerígenas que presentan una elevada actividad glucolítica debido a la represión bioenergética de sus mitocondrias. La huella bioenergética estimada por la razón entre las proteínas β-F1-ATPasa y GAPDH es un índice proteómico que informa de la actividad metabólica de los tumores y células cancerígenas y permite estimar la agresividad tumoral. Además, la huella bioenergética proporciona una diana común a neoplasias muy diversas para el desarrollo de nuevas terapias antitumorales ya que informa de la resistencia de las células cancerígenas a la quimioterapia. En este artículo de revisión destacamos los diferentes mecanismos que pueden alterar la actividad bioenergética de la mitocondria en cáncer, especialmente aquellos que afectan a la H+-ATP sintasa y que promueven el fenotipo Warburg de las células cancerígenas

The H+-ATP synthase: A gate to ROS-mediated cell death or cell survival

This article is part of a Special Issue entitled: 18th European Bioenergetic ConferenceCellular oxidative stress results from the increased generation of reactive oxygen species and/or the dysfunction of the antioxidant systems. Most intracellular reactive oxygen species derive from superoxide radical although the majority of the biological effects of reactive oxygen species are mediated by hydrogen peroxide. In this contribution we overview the major cellular sites of reactive oxygen species production, with special emphasis in the mitochondrial pathways. Reactive oxygen species regulate signaling pathways involved in promoting survival and cell death, proliferation, metabolic regulation, the activation of the antioxidant response, the control of iron metabolism and Ca2 + signaling. The reversible oxidation of cysteines in transducers of reactive oxygen species is the primary mechanism of regulation of the activity of these proteins. Next, we present the mitochondrial H+-ATP synthase as a core hub in energy and cell death regulation, defining both the rate of energy metabolism and the reactive oxygen species-mediated cell death in response to chemotherapy. Two main mechanisms that affect the expression and activity of the H+-ATP synthase down-regulate oxidative phosphorylation in prevalent human carcinomas. In this context, we emphasize the prominent role played by the ATPase Inhibitory Factor 1 in human carcinogenesis as an inhibitor of the H+-ATP synthase activity and a mediator of cell survival. The ATPase Inhibitory Factor 1 promotes metabolic rewiring to an enhanced aerobic glycolysis and the subsequent production of mitochondrial reactive oxygen species. The generated reactive oxygen species are able to reprogram the nucleus to support tumor development by arresting cell death. Overall, we discuss the cross-talk between reactive oxygen species signaling and mitochondrial function that is crucial in determining the cellular fateWork in the authors’ laboratory was supported by grants from the Ministerio de Educación y Ciencia (BFU2010-18903), by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII and by Comunidad de Madrid (S/2011-BMD-2402), Spain. The CBMSO receives an institutional grant from Fundación Ramón Arece

Mitochondria-mediated energy adaption in cancer: The H+-ATP synthase-geared switch of metabolism in human tumors

Significance: Since the signing of the National Cancer Act in 1971, cancer still remains a major cause of death despite significant progresses made in understanding the biology and treatment of the disease. After many years of ostracism, the peculiar energy metabolism of tumors has been recognized as an additional phenotypic trait of the cancer cell. Recent Advances: While the enhanced aerobic glycolysis of carcinomas has already been translated to bedside for precise tumor imaging and staging of cancer patients, accepting that an impaired bioenergetic function of mitochondria is pivotal to understand energy metabolism of tumors and in its progression is debated. However, mitochondrial bioenergetics and cell death are tightly connected. Critical Issues: Recent clinical findings indicate that H+-ATP synthase, a core component of mitochondrial oxidative phosphorylation, is repressed at both the protein and activity levels in human carcinomas. This review summarizes the relevance that mitochondrial function has to understand energy metabolism of tumors and explores the connection between the bioenergetic function of the organelle and the activity of mitochondria as tumor suppressors. Future Directions: The reversible nature of energy metabolism in tumors highlights the relevance that the microenvironment has for tumor progression. Moreover, the stimulation of mitochondrial activity or the inhibition of glycolysis suppresses tumor growth. Future research should elucidate the mechanisms promoting the silencing of oxidative phosphorylation in carcinomas. The aim is the development of new therapeutic strategies tackling energy metabolism to eradicate tumors or at least, to maintain tumor dormancy and transform cancer into a chronic disease. Antioxid. Redox Signal. 19, 285-298Supported by JCI2009-03918 Juan de la Cierva Grant, Ministerio de Educación y Ciencia, Spain. Work in the authors’ laboratory was supported by grants from the Ministerio de Educación y Ciencia (BFU2010-18903), by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII and by Comunidad de Madrid (S2011/BMD-2402), Spain. The CBMSO receives an institutional grant from Fundación Ramón Arece

Degradation of IF1 controls energy metabolism during osteogenic differentiation of stem cells

Differentiation of human mesenchymal stem cells (hMSCs) requires the rewiring of energy metabolism. Herein, we demonstrate that the ATPase inhibitory factor 1 (IF1) is expressed in hMSCs and in prostate and colon stem cells but is not expressed in the differentiated cells. IF1 inhibits oxidative phosphorylation and regulates the activity of aerobic glycolysis in hMSCs. Silencing of IF1 in hMSCs mimics the metabolic changes observed in osteocytes and accelerates cellular differentiation. Activation of IF1 degradation acts as the switch that regulates energy metabolism during differentiation. We conclude that IF1 is a stemness marker important for maintaining the quiescence stateThis work was supported by grants from the Ministerio de Educación y Ciencia (BFU2010-18903), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, and Comunidad de Madrid (S2011/BMD-2402), Spai

AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells

Reprogramming of energetic metabolism is a phenotypic trait of cancer in which mitochondrial dysfunction represents a key event in tumour progression. In the present study, we show that the acquisition of the tumour-promoting phenotype in colon cancer HCT116 cells treated with oligomycin to inhibit ATP synthase is exerted by repression of the synthesis of nuclear-encoded mitochondrial proteins in a process that is regulated at the level of translation. Remarkably, the synthesis of glycolytic proteins is not affected in this situation. Changes in translational control of mitochondrial proteins are signalled by the activation of AMPK (AMP-activated protein kinase) and the GCN2 (general control non-derepressible 2) kinase, leading also to the activation of autophagy. Changes in the bioenergetic function of mitochondria are mimicked by the activation of AMPK and the silencing of ATF4 (activating transcription factor 4). These findings emphasize the relevance of translational control for normal mitochondrial function and for the progression of cancer. Moreover, they demonstrate that glycolysis and oxidative phosphorylation are controlled at different levels of gene expression, offering the cell a mechanistic safeguard strategy for metabolic adaptation under stressful conditions.</jats:p

Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The definitive publisher-authenticated version Carcinogenesis 2006 27(5):925-935 is available at: http://dx.doi.org/10.1093/carcin/bgi315There is a large body of clinical data documenting that most human carcinomas contain reduced levels of the catalytic subunit of the mitochondrial H+-ATP synthase. In colon and lung cancer this alteration correlates with a poor patient prognosis. Furthermore, recent findings in colon cancer cells indicate that downregulation of the H+-ATP synthase is linked to the resistance of the cells to chemotherapy. However, the mechanism by which the H+-ATP synthase participates in cancer progression is unknown. In this work, we show that inhibitors of the H+-ATP synthase delay staurosporine (STS)-induced cell death in liver cells that are dependent on oxidative phosphorylation for energy provision whereas it has no effect on glycolytic cells. Efficient execution of cell death requires the generation of reactive oxygen species (ROS) controlled by the activity of the H+-ATP synthase in a process that is concurrent with the rapid disorganization of the cellular mitochondrial network. The generation of ROS after STS treatment is highly dependent on the mitochondrial membrane potential and most likely caused by reverse electron flow to Complex I. The generated ROS promote the carbonylation and covalent modification of cellular and mitochondrial proteins. Inhibition of the activity of the H+-ATP synthase blunted ROS production prevented the oxidation of cellular proteins and the modification of mitochondrial proteins delaying the release of cytochrome c and the execution of cell death. The results in this work establish the downregulation of the H+-ATP synthase, and thus of oxidative phosphorylation, as part of the molecular strategy adapted by cancer cells to avoid ROS-mediated cell death. Furthermore, the results provide a mechanistic explanation to understand chemotherapeutic resistance of cancer cells that rely on glycolysis as the main energy provision pathway.G.S. and M.M-D. were supported by pre-doctoral fellowships from the Ministerio de Ciencia y Tecnología. This work was supported by grants from the Ministerio de Sanidad y Consumo (PI041255), Comunidad de Madrid (SAL/0026/2004) and Ministerio de Ciencia y Tecnología (BMC2001-0710). The CBMSO receives an institutional grant from Fundación Ramón Areces.Peer reviewe

miR-127-5p targets the 3'UTR of human β-F1-ATPase mRNA and inhibits its translation

IMW and IMR are the recipients of pre-doctoral fellowships from the Plan de Formación de Profesorado Universitario (AP2007-03035) from the Ministerio de Educación and JAE-CSIC, respectively. The work was supported by grants from the Ministerio de Educación y Ciencia (BFU2010- 18903), by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII and by Comunidad de Madrid (S2011/BMD-2402), Spain. The CBMSO receives an institutional grant from Fundación Ramón Arece