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Mitochondrial metabolism has emerged as a promising target against the mechanisms of tumor growth. Herein, we have screened an FDA-approved library to identify drugs that inhibit mitochondrial respiration. The β1-blocker nebivolol specifically hinders oxidative phosphorylation in cancer cells by concertedly inhibiting Complex I and ATP synthase activities. Complex I inhibition is mediated by interfering the phosphorylation of NDUFS7. Inhibition of the ATP synthase is exerted by the overexpression and binding of the ATPase Inhibitory Factor 1 (IF1) to the enzyme. Remarkably, nebivolol also arrests tumor angiogenesis by arresting endothelial cell proliferation. Altogether, targeting mitochondria and angiogenesis triggers a metabolic and oxidative stress crisis that restricts the growth of colon and breast carcinomas. Nebivolol holds great promise to be repurposed for the treatment of cancer patients. Targeting mitochondrial metabolism in cancer cells has shown promising therapeutic potential. Here, the authors screen FDA-approved compound library and show that the β1-blocker nebivolol inhibits oxidative phosphorylation and angiogenesis in cancer cells and can be re-purposed for cancer therapy. [ABSTRACT FROM AUTHOR]

Cancer cells reprogram energy metabolism by boosting aerobic glycolysis as a main pathway for the provision of metabolic energy and of precursors for anabolic purposes. Accordingly, the relative expression of the catalytic subunit of the mitochondrial H+-ATP synthase--the core hub of oxidative phosphorylation--is downregulated in human carcinomas when compared with its expression in normal tissues. Moreover, some prevalent carcinomas also upregulate the ATPase inhibitory factor 1 (IF1), which is the physiological inhibitor of the H+-ATP synthase. IF1 overexpression, both in cells in culture and in tissue-specific mouse models, is sufficient to reprogram energy metabolism to an enhanced glycolysis by limiting ATP production by the H+-ATP synthase. Furthermore, the IF1-mediated inhibition of the H+-ATP synthase promotes the production of mitochondrial ROS (mtROS). mtROS modulate signaling pathways favoring cellular proliferation and invasion, the activation of antioxidant defenses, resistance to cell death, and modulation of the tissue immune response, favoring the acquisition of several cancer traits. Consistently, IF1 expression is an independent marker of cancer prognosis. By contrast, inhibition of the H+-ATP synthase by α-ketoglutarate and the oncometabolite 2-hydroxyglutarate, reduces mTOR signaling, suppresses cancer cell growth, and contributes to lifespan extension in several model organisms. Hence, the H+-ATP synthase appears as a conserved hub in mitochondria-to-nucleus signaling controlling cell fate. Unraveling the molecular mechanisms responsible for IF1 upregulation in cancer and the signaling cascades that are modulated by the H+-ATP synthase are of utmost interest to decipher the metabolic and redox circuits contributing to cancer origin and progression. [ABSTRACT FROM AUTHOR]

A key transducer in energy conservation and signaling cell death is the mitochondrial H+- ATP synthase. The expression of the ATPase inhibitory factor 1 (IF1) is a strategy used by cancer cells to inhibit the activity of the H+- ATP synthase to generate a ROS signal that switches on cellular programs of survival. We have generated a mouse model expressing a mutant of human IF1 in brain neurons to assess the role of the H+- ATP synthase in cell death in vivo. The expression of hIF1 inhibits the activity of oxidative phosphorylation and mediates the shift of neurons to an enhanced aerobic glycolysis. Metabolic reprogramming induces brain preconditioning affording protection against quinolinic acid-induced excitotoxicity. Mechanistically, preconditioning involves the activation of the Akt/p70S6K and PARP repair pathways and Bcl- xL protection from cell death. Overall, our findings provide the first in vivo evidence highlighting the H+- ATP synthase as a target to prevent neuronal cell death. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (β-F1-ATPase). The bioenergetic signature is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the bioenergetic signature of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti-metabolite, 5-fluorouracil (5-FU). Methods: The bioenergetic signature of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the bioenergetic signature and the cell death response. In vivo tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells. Results: We demonstrate that the bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable. Conclusions: Overall, we suggest that the determination of the bioenergetic signature of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression. [ABSTRACT FROM AUTHOR]

The contribution that mitochondrial bioenergetics could have in cancer development is debated. Here, we have generated HCT116-derived colocarcinoma cell lines expressing different levels of the β catalytic subunit of the mitochondrial H+-adenosine triphosphate synthase to assess the contribution of mitochondrial bioenergetics in colon cancer progression. The generated cells exhibit large ultrastructural, transcriptomic, proteomic and functional differences in their mitochondria and in their in vivo tumor forming capacity. We show that the activity of oxidative phosphorylation defines the rate of glucose utilization by aerobic glycolysis. The aggressive cellular phenotype, which is highly glycolytic, is bound to the deregulated expression of genes involved in metabolic processes, the regulation of the cell cycle, apoptosis, angiogenesis and cell adhesion. Remarkably, the molecular and ultrastructural analysis of the tumors derived from the three HCT116 cell lines under study highlight that tumor promotion inevitably requires the selection of cancer cells with a repressed biogenesis and functional activity of mitochondria, i.e. the highly glycolytic phenotype is selected for tumor development. The tumor forming potential of the cells is a non-genetically acquired condition that provides the cancer cell with a cell-death resistant phenotype. An abrogated mitochondrial respiration contributes to a diminished potential for reactive oxygen species signaling in response to 5-fluorouracil treatment. Treatment of cancer cells with dichloroacetate partially restores the functional differentiation of mitochondria and promotes tumor regression, emphasizing the reversible nature of the metabolic trait of cancer. [ABSTRACT FROM PUBLISHER]

Abstract: Recently, the inevitable metabolic reprogramming experienced by cancer cells as a result of the onset of cellular proliferation has been added to the list of hallmarks of the cancer cell phenotype. Proliferation is bound to the synchronous fluctuation of cycles of an increased glycolysis concurrent with a restrained oxidative phosphorylation. Mitochondria are key players in the metabolic cycling experienced during proliferation because of their essential roles in the transduction of biological energy and in defining the life–death fate of the cell. These two activities are molecularly and functionally integrated and are both targets of commonly altered cancer genes. Moreover, energetic metabolism of the cancer cell also affords a target to develop new therapies because the activity of mitochondria has an unquestionable tumor suppressor function. In this review, we summarize most of these findings paying special attention to the opportunity that translation of energetic metabolism into the clinics could afford for the management of cancer patients. More specifically, we emphasize the role that mitochondrial β-F1-ATPase has as a marker for the prognosis of different cancer patients as well as in predicting the tumor response to therapy. [Copyright &y& Elsevier]

Metabolic reprogramming of cancer cells is a phenotypic trait necessary to promote proliferation and survival. Despite past controversies, recent transcriptomic, proteomic, functional and structural studies of mitochondria of the cancer cell indicate that an impaired biogenesis and activity of the organelle is required for the development of some tumors. Cancer aggressiveness can be estimated by its bioenergetic signature, a protein ratio that correlates the expression of β-F1-ATPase of oxidative phosphorylation relative to the glycolytic GAPDH. The bioenergetic signature also provides a gauge that informs of the metabolic activity of tumors and cancer cells as well as of the response to chemotherapy. The convergence of different epithelial tumors on the same bioenergetic signature supports that it provides an important tool and common target for cancer therapy. We stress that targeting the energetic metabolism of tumors affords a valuable strategy to combat the disease. © 2010 IUBMB IUBMB Life 62(7): 554–560, 2010 [ABSTRACT FROM AUTHOR]

Abstract: The mitochondrial H+-ATP synthase is a bottleneck component in the provision of metabolic energy by oxidative phosphorylation. The expression of its catalytic subunit (β-F1-ATPase) is stringently controlled at post-transcriptional levels during oncogenesis, the cell cycle and in development. Here we show that miR-127-5p targets the 3′UTR of β-F1-ATPase mRNA (β-mRNA) significantly reducing its translational efficiency without affecting β-mRNA abundance. Despite the reduced expression of β-F1-ATPase in most human carcinomas, we observed no expression of miR-127-5p in different human cancer cell lines, minimizing the potential role of miR-127-5p as a regulator of the bioenergetic activity of mitochondria in cancer. In contrast, miR-127-5p is highly over-expressed in the human fetal liver. Consistent with previous findings in the rat, the expression of β-F1-ATPase in the human liver also seems to be controlled at post-transcriptional levels during development, what might suggest a role for miR-127-5p in controlling β-mRNA translation and thus in defining the bioenergetic activity of human liver mitochondria. Moreover, immunolocalization techniques and subcellular fractionation experiments using different antibodies against β-F1-ATPase reveal that the ectopic expression of β-F1-ATPase at the cell surface of the hepatocytes and HepG2 cells is negligible or stands for scrutiny. [Copyright &y& Elsevier]

Summary: Recent findings indicate that prevalent human carcinomas overexpress the mitochondrial ATPase Inhibitory Factor 1 (IF1). Overexpression of IF1 inhibits the synthase activity of the mitochondrial H+-ATP synthase and plays a crucial role in metabolic adaptation of cancer cells to enhanced aerobic glycolysis. Herein, we demonstrate that IF1 overexpression in colon cancer cells triggers mitochondrial hyperpolarization and the subsequent production of superoxide radical, a reactive oxygen species (ROS). ROS are required to promote the transcriptional activation of the NFκB pathway via phosphorylation-dependent IκBα degradation. Activation of NFκB results in a cellular adaptive response that includes proliferation and Bcl-xL mediated resistance to drug-induced cell death. Quenching the mitochondrial production of ROS prevents the activation of NFκB and abolishes the IF1-mediated cellular adaptive response. Overall, our findings provide evidence linking the activity of a mitochondrial protein with retrograde signaling to the nucleus to promote cellular proliferation and survival. [Copyright &y& Elsevier]