Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

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.

Download Full-text

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

Endocrine Related Cancer ◽

10.1530/erc-16-0142 ◽

2016 ◽

Vol 23 (9) ◽

pp. 747-758 ◽

Cited By ~ 14

Author(s):

Zara Zelenko ◽

Emily Jane Gallagher ◽

Irini Markella Antoniou ◽

Deepali Sachdev ◽

Anupma Nayak ◽

...

Keyword(s):

Insulin Receptor ◽

Cancer Cells ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Mortality Data ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Insulin Resistant ◽

Human Cancer Cells

Type 2 diabetes (T2D) is associated with increased cancer risk and cancer-related mortality. Data herein show that we generated an immunodeficient hyperinsulinemic mouse by crossing theRag1−/−mice, which have no mature B or T lymphocytes, with the MKR mouse model of T2D to generate theRag1−/−(Rag/WT) andRag1−/−/MKR+/+(Rag/MKR) mice. The female Rag/MKR mice are insulin resistant and have significantly higher nonfasting plasma insulin levels compared with the Rag/WT controls. Therefore, we used these Rag/MKR mice to investigate the role of endogenous hyperinsulinemia on human cancer progression. In this study, we show that hyperinsulinemia in the Rag/MKR mice increases the expression of mesenchymal transcription factors,TWIST1andZEB1, and increases the expression of the angiogenesis marker, vascular endothelial growth factor A (VEGFA). We also show that silencing the insulin receptor (IR) in the human LCC6 cancer cells leads to decreased tumor growth and metastases, suppression of mesenchymal markers vimentin, SLUG, TWIST1 and ZEB1, suppression of angiogenesis markers,VEGFAandVEGFD, and re-expression of the epithelial marker, E-cadherin. The data in this paper demonstrate that IR knockdown in primary tumors partially reverses the growth-promoting effects of hyperinsulinemia as well as highlighting the importance of the insulin receptor signaling pathway in cancer progression, and more specifically in epithelial–mesenchymal transition.

Download Full-text

Mitochondrial Complex I Inhibitors and Forced Oxidative Phosphorylation Synergize in Inducing Cancer Cell Death

International Journal of Cell Biology ◽

10.1155/2013/243876 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 31

Author(s):

Roberta Palorini ◽

Tiziana Simonetto ◽

Claudia Cirulli ◽

Ferdinando Chiaradonna

Keyword(s):

Cell Death ◽

Oxidative Phosphorylation ◽

Cancer Cells ◽

Cancer Cell ◽

Complex I ◽

Mitochondrial Complex I ◽

Low Doses ◽

Mitochondrial Complex ◽

Cancer Cell Death ◽

Glucose Depletion

Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS) for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.

Download Full-text