Journal
CELL CYCLE
Volume 12, Issue 1, Pages 172-182Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.23058
Keywords
chemoprevention; Metformin; mitochondrial dysfunction; breast cancer; tumor growth; UCP; mitochondrial uncoupling proteins; autophagy; ketone body production; fatty acid beta-oxidation; ATP-rich vesicles
Categories
Funding
- Breast Cancer Alliance
- Margaret Q. Landenberger Research Foundation
- National Institute on Alcohol Abuse and Alcoholism (NIAAA) [T32 AA007467]
- Breakthrough Breast Cancer in the UK
- European Research Council
- Breast Cancer Now [MAN-Q1] Funding Source: researchfish
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [T32AA007467] Funding Source: NIH RePORTER
Ask authors/readers for more resources
Metformin is a well-established diabetes drug that prevents the onset of most types of human cancers in diabetic patients, especially by targeting cancer stem cells. Metformin exerts its protective effects by functioning as a weak mitochondrial poison, as it acts as a complex I inhibitor and prevents oxidative mitochondrial metabolism (OXPHOS). Thus, mitochondrial metabolism must play an essential role in promoting tumor growth. To determine the functional role of mitochondrial health in breast cancer pathogenesis, here we used mitochondrial uncoupling proteins (UCPs) to genetically induce mitochondrial dysfunction in either human breast cancer cells (MDA-MB-231) or cancer-associated fibroblasts (hTERT-BJ1 cells). Our results directly show that all three UCP family members (UCP-1/2/3) induce autophagy and mitochondrial dysfunction in human breast cancer cells, which results in significant reductions in tumor growth. Conversely, induction of mitochondrial dysfunction in cancer-associated fibroblasts has just the opposite effect. More specifically, overexpression of UCP-1 in stromal fibroblasts increases beta-oxidation, ketone body production and the release of ATP-rich vesicles, which fuels tumor growth by providing high-energy nutrients in a paracrine fashion to epithelial cancer cells. Hence, the effects of mitochondrial dysfunction are truly compartment-specific. Thus, we conclude that the beneficial anticancer effects of mitochondrial inhibitors (such as metformin) may be attributed to the induction of mitochondrial dysfunction in the epithelial cancer cell compartment. Our studies identify cancer cell mitochondria as a clear target for drug discovery and for novel therapeutic interventions.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available