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

Abstract

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-1α and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1α and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up 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-1β 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-1α, PGC-1β, mitoNEET 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.

NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth

“…1A). These findings are supported by mRNA expression studies of NEET proteins in breast cancer cells (23)(24)(25), and suggest a role for NEET proteins in promoting mitochondrial biogenesis and autophagy resistance in cancer cells (23).…”

“…Interestingly, levels of mNT and NAF-1 mRNA are increased significantly in many different human cancer cells (23)(24)(25). The involvement of NAF-1 and mNT in mitochondrial metabolism and homeostasis, as well as in autophagy regulation, points to a possible role for these proteins in cell transformation.…”

“…NAF-1 is also localized to the endoplasmic reticulum, where it interacts with BCL-2 and Beclin 1 to regulate autophagy and apoptosis (8-13). Deficiency in mNT causes the accumulation of iron and ROS in mitochondria of animal and plant cells, and deficiency in NAF-1 results in decreased mitochondrial function and stability, as well as activation of autophagy in mice and human cells (13-16, 20, 21).Interestingly, levels of mNT and NAF-1 mRNA are increased significantly in many different human cancer cells (23)(24)(25). The involvement of NAF-1 and mNT in mitochondrial metabolism and homeostasis, as well as in autophagy regulation, points to a possible role for these proteins in cell transformation.…”

Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism

“…44 Thus, alcohol consumption induces that same metabolic phenotype, which is related to the onset of hereditary ovarian and breast cancers, by promoting oxidative mitochondrial metabolism (OXPHOS) in epithelial cancer cells. 45,46 Ketone body re-utilization has also been shown to confer tamoxifen resistance upon MCF7 cells, consistent with our current findings that ethanol can suppress ER-α expression in MCF7 cells during co-culture with fibroblasts. 47 And, loss of stromal Cav-1 is a predictor of treatment failure in tamoxifentreated ER(+) breast cancer patients.…”

Mitochondrial dysfunction in breast cancer cells prevents tumor growth

“…27,32,47 Finally, genetic induction of mitochondrial biogenesis in cancer cells (by expression of PGC1-α/β; POLRMT; or MitoNEET) promotes tumorigenesis. 48 Thus, we have identified (1) stromal ketone production and (2) mitochondrial biogenesis in epithelial cancer cells as two key metabolic components which are energetically driving tumor cell growth and cancer cell metastasis. 31,32 Our current studies predict that mitochondrial inhibitors would be a beneficial anticancer strategy, as they would induce mitochondrial dysfunction in epithelial cancer cells.…”