Represión de la diferenciación mitocondrial en progresión tumoral y en senescencia

Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 20-07-200

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

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

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

Sensitivity to anti-Fas is independent of increased cathepsin D activity and adrenodoxin reductase expression occurring in NOS-3 overexpressing HepG2 cells

© 2015 Elsevier B.V. Stable overexpression of endothelial nitric oxide synthase (NOS-3) in HepG2 cells (4TO-NOS) leads to increased nitro-oxidative stress and upregulation of the cell death mediators p53 and Fas. Thus, NOS-3 overexpression has been suggested as a useful antiproliferative mechanism in hepatocarcinoma cells. We aimed to identify the underlying mechanism of cell death induced by NOS-3 overexpression at basal conditions and with anti-Fas treatment. The intracellular localization of NOS-3, the nitro-oxidative stress and the mitochondrial activity were analysed. In addition, the protein expression profile in 4TO-NOS was screened for differentially expressed proteins potentially involved in the induction of apoptosis. NOS-3 localization in the mitochondrial outer membrane was not associated with changes in the respiratory cellular capacity, but was related to the mitochondrial biogenesis increase and with a higher protein expression of mitochondrial complex IV. Nitro-oxidative stress and cell death in NOS-3 overexpressing cells occurred with the expression increase of pro-apoptotic genes and a higher expression/activity of the enzymes adrenodoxin reductase mitochondrial (AR) and cathepsin D (CatD). CatD overexpression in 4TO-NOS was related to the apoptosis induction independently of its catalytic activity. In addition, CatD activity inhibition by pepstatin A was not effective in blocking apoptosis induced by anti-Fas. In summary, NOS-3 overexpression resulted in an increased sensitivity to anti-Fas induced cell death, independently of AR expression and CatD activity.Instituto de Salud Carlos III (FIS 09/00185). G. Ferrín was supported by the Networked Biomedical Research Center Hepatic and Digestive Diseases (CIBEREHD)Peer Reviewe

A message emerging from development: the repression of mitochondrial β-F1-ATPase expression in cancer

The original publication is available at www.springerlink.com http://dx.doi.org/10.1007/s10863-007-9087-9Mitochondrial research has experienced a considerable boost during the last decade because organelle malfunctioning is in the genesis and/or progression of a vast array of human pathologies including cancer. The renaissance of mitochondria in the cancer field has been promoted by two main facts: (1) the molecular and functional integration of mitochondrial bioenergetics with the execution of cell death and (2) the implementation of 18FDG-PET for imaging and staging of tumors in clinical practice. The latter, represents the bed-side translational development of the metabolic hallmark that describes the bioenergetic phenotype of most cancer cells as originally predicted at the beginning of previous century by Otto Warburg. In this minireview we will briefly summarize how the study of energy metabolism during liver development forced our encounter with Warburg’s postulates and prompted us to study the mechanisms that regulate the biogenesis of mitochondria in the cancer cellThis review article was written while the research activity in the authors’ laboratory was supported by grants from the Ministerio de Sanidad (PI041255), Educación y Ciencia (SAF2005-4001) and Fundación Mutua Madrileña. The CBMSO is the recipient of an institutional grant from Fundación Ramón ArecesPeer reviewe

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

IF1 reprograms energy metabolism and signals the oncogenic phenotype in cancer

Comment on: Formentini L, et al. Mol Cell 2012; 45:731-42

Hif-1α knockdown reduces glycolytic metabolism and induces cell death of human synovial fibroblasts under normoxic conditions

[Abstract] Increased glycolysis and HIF-1α activity are characteristics of cells under hypoxic or inflammatory conditions. Besides, in normal O2 environments, elevated rates of glycolysis support critical cellular mechanisms such as cell survival. The purpose of this study was to analyze the contribution of HIF-1α to the energy metabolism and survival of human synovial fibroblasts (SF) under normoxic conditions. HIF-1α was silenced using lentiviral vectors or small-interfering RNA (siRNA) duplexes. Expression analysis by qRT-PCR and western blot of known HIF-1α target genes in hypoxia demonstrated the presence of functional HIF-1α in normoxic SF and confirmed the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a HIF-1α target even in normoxia. HIF-1α silencing induced apoptotic cell death in cultured SF and, similarly, treatment with glycolytic, but not with OXPHOS inhibitors, induced SF death. Finally, in vivo HIF-1α targeting by siRNA showed a significant reduction in the viability of human SF engrafted into a murine air pouch. Our results demonstrate that SF are highly dependent on glycolytic metabolism and that HIF-1α plays a regulatory role in glycolysis even under aerobic conditions. Local targeting of HIF-1α provides a feasible strategy to reduce SF hyperplasia in chronic arthritic diseases.Instituto de Salud Carlos III; FIS 12/439Instituto de Salud Carlos III; RETICS RD12/009Instituto de Salud Carlos III; CP13/00014Comunidad de Madrid; RAPHYME-CM S2010/BMD235