title: Mitochondrial dysfunction in breast cancer cells prevents tumor growth: understanding chemoprevention with metformin.
abstract: 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 β-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.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Sanchez-Alvarez
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lamb
authors.forename: James
authors.initials: J
authors.lastname: Hulit
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gandara
authors.forename: Marina
authors.initials: M
authors.lastname: Sartini
authors.forename: Emanuel
authors.initials: E
authors.lastname: Rubin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051242:Caveolin 1 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D018920:Coculture Techniques; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D000970:Antineoplastic Agents; D051242:Caveolin 1; D007473:Ion Channels; D007657:Ketone Bodies; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D008687:Metformin