Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance

Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would fuel enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1 alpha and MitoNEE T, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1 alpha and MitoNEE T increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to similar to 3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1 beta and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial power in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1 alpha, PGC-1 beta, mitoNEE T and POLRMT should all be considered as tumor promoters or metabolic oncogenes. Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial poison) prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells.