title: Coordinated Upregulation of Mitochondrial Biogenesis and Autophagy in Breast Cancer Cells: The Role of Dynamin Related Protein-1 and Implication for Breast Cancer Treatment.
abstract: Overactive mitochondrial fission was shown to promote cell transformation and tumor growth. It remains elusive how mitochondrial quality is regulated in such conditions. Here, we show that upregulation of mitochondrial fission protein, dynamin related protein-1 (Drp1), was accompanied with increased mitochondrial biogenesis markers (PGC1α, NRF1, and Tfam) in breast cancer cells. However, mitochondrial number was reduced, which was associated with lower mitochondrial oxidative capacity in breast cancer cells. This contrast might be owing to enhanced mitochondrial turnover through autophagy, because an increased population of autophagic vacuoles engulfing mitochondria was observed in the cancer cells. Consistently, BNIP3 (a mitochondrial autophagy marker) and autophagic flux were significantly upregulated, indicative of augmented mitochondrial autophagy (mitophagy). The upregulation of Drp1 and BNIP3 was also observed in vivo (human breast carcinomas). Importantly, inhibition of Drp1 significantly suppressed mitochondrial autophagy, metabolic reprogramming, and cancer cell viability. Together, this study reveals coordinated increase of mitochondrial biogenesis and mitophagy in which Drp1 plays a central role regulating breast cancer cell metabolism and survival. Given the emerging evidence of PGC1αcontributing to tumor growth, it will be of critical importance to target both mitochondrial biogenesis and mitophagy for effective cancer therapeutics.
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Fralin Life Science Institute, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Fralin Life Science Institute, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Longhua
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Fralin Life Science Institute, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Louise D
authors.initials: LD
authors.lastname: Zheng
authors.affiliation: Department of Microbiology and Immunology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Payne
authors.affiliation: Department of Microbiology and Immunology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Masoud H
authors.identifier: 0000-0001-7511-2953
authors.initials: MH
authors.lastname: Manjili
authors.affiliation: Department of Pathology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Idowu
authors.affiliation: Department of Statistics, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Fralin Life Science Institute, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schmelz
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Fralin Life Science Institute, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Zhiyong
authors.identifier: 0000-0001-7615-9788
authors.initials: Z
authors.lastname: Cheng
mesh_terms: D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001678:Organelle Biogenesis; D010084:Oxidation-Reduction / Q000187:drug effects; D052999:Quinazolinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D052999:Quinazolinones; D012333:RNA, Messenger; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins