Untuning the tumor metabolic machine: Targeting cancer metabolism: A bedside lesson
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA, the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.Nature medicine (Impact Factor: 27.36). 07/2012; 18(7):1022-3. DOI: 10.1038/nm.2870
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- "Recent studies have indicated that the anti-proliferative effects of metformin in cancer cells are highly dependent on the glucose concentration in the extracellular milieu (Wahdan-Alaswad et al. 2013, Zordoky et al. 2014). It has been demonstrated that metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation (Birsoy et al. 2012, Zordoky et al. 2014). Experimental in vitro and in vivo studies have demonstrated that use of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) in combination with metformin leads to significant cell death associated with a decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy (Cheong et al. 2011). "
ABSTRACT: Metformin inhibits thyroid cancer cell growth. We sought to determine if variable glucose concentrations in medium alter the anti-cancer efficacy of metformin. Thyroid cancer cells (FTC133 and BCPAP) were cultured in high-glucose (20 mM) and low-glucose (5 mM) medium before treatment with metformin. Cell viability and apoptosis assays were performed. Expression of glycolytic genes was examined by real-time PCR, Western blot and immunostaining. Metformin inhibited cellular proliferation in high-glucose medium and induced cell death in low-glucose medium. In low-, but not in high-glucose medium, metformin induced endoplasmic reticulum stress, autophagy, and cytoplasmic swelling that is typical for oncosis. At micromolar concentrations metformin induced phosphorylation of AMP-activated protein kinase and block p-pS6 in low-glucose medium. Metformin increased the rate of glucose consumption from the medium and prompted medium acidification. Medium supplementation with glucose reversed metformin-inducible morphological changes. Treatment with an inhibitor of glycolysis (2-deoxyglycose) increased thyroid cancer cell sensitivity to metformin. The combination of 2DG with metformin (25 μM) led to cell death. Thyroid cancer cell lines were characterized by over-expression of glycolytic genes, and metformin decreased the protein level of pyruvate kinase muscle (PKM2). PKM2 expression was detected in recurrent thyroid cancer tissue samples. In conclusion, we have demonstrated that the glucose concentration in the cellular milieu is a factor modulating metformin's anti-cancer activity. These data suggest that the combination of metformin with inhibitors of glycolysis could represent a new strategy for the treatment of thyroid cancer.
- "For example, Anastasiou et al.showed recently that the enzyme pyruvate kinase M2 (PKM2), which is the predominant pyruvate kinase found in cancer cells, is crucial for maintaining cellular redox homeostasis. Furthermore, recent studies suggest that metabolic enzymes can act as tumor suppressors (e.g., fumarate hydratase and succinate dehydrogenase ), or oncogenes (e.g., mutant isocitrate dehydrogenase 1 and 2)678. These recent studies confirmed that altered metabolism is indeed a hallmark of cancer, and suggested that the changes in metabolism in cancer cells are much more complex than that was suggested initially. "
Conference Paper: Molecular mechanisms underlying lung cancer progression
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- "Alternatively, metformin may act in a cancer cell autonomous manner. Metformin is known to inhibit mitochondrial complex I in vitro (Ota et al., 2009; El-Mir et al., 2000; Owen et al., 2000) and it is thus possible that this targeting of the electron transport chain could inhibit tumor cell growth (Birsoy et al., 2012). This latter hypothesis has been questioned as cancer cells have the ability to survive on ATP produced exclusively by glycolysis. "
ABSTRACT: Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I. DOI: http://dx.doi.org/10.7554/eLife.02242.001