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

作者：Salem Ahmed F; Whitaker Menezes Diana; Howell Anthony; Sotgia Federica^*; Lisanti Michael P

来源：Cell Cycle, 2012, 11(22): 4174-4180.

DOI：10.4161/cc.22376

• cancer metabolism
• mitochondrial biogenesis
• oxidative phosphorylation
• OXPHOS
• autophagy resistance
• angiogenesis
• two-compartment tumor metabolism

Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would %26quot;fuel%26quot; 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 %26quot;power%26quot; 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 %26quot;metabolic oncogenes.%26quot; Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial %26quot;poison%26quot;) 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.

• 出版日期2012-11-15