title: Nutrient Starvation Sensitizes Human Ovarian Cancer SKOV3 Cells to BH3 Mimetic via Modulation of Mitochondrial Dynamics.
abstract: The aberrant proliferation of tumor cells necessitates compensatory changes in tumor metabolic processes. Previous studies on tumor growth and metabolism have established a relationship between nutrient stress and Bcl-2 anti-apoptotic proteins, although the mechanisms connecting these processes remain unclear. We induced nutrient deprivation in human ovarian cancer SKOV3 cells by culturing cells in Earle's balanced salt solution (EBSS) as a starvation model. We used EBSS treatment with the BH3 domain of Bcl-2 family proteins (BH3) mimetic ABT737, which targets Bcl-2/Bcl-xL, to examine mitochondrial dynamics and the interactive regulatory mechanisms between nutrition and Bcl-2 proteins. We found that EBSS combined with ABT737 can promote SKOV3 cells to undergo apoptosis and convert tubular mitochondria into small, fragmented morphologies. Bcl-2 family proteins participated in the regulation of mitochondrial fusion and fission through apoptosis, and the decrease of Mcl-1 expression was the key to ABT737 sensitization. Our findings showed that nutrient stress could sensitize SKOV3 cells to ABT737 via regulation of the mitochondrial dynamic balance and interaction of Bcl-2 family proteins. Our data suggest that nutrient starvation combined with the BH3 mimetic ABT737 could reduce the required effective dose of ABT737, and that inhibition of Bcl-2 and Mcl-1 together with nutrient starvation could serve as an effective strategy for the treatment of human ovarian cancer. Anat Rec, 300:326-339, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
authors.forename: Si
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Biological Engineering, College of Pharmacy, Jilin University, Changchun, 130021, People's Republic of China.
authors.forename: Song
authors.initials: S
authors.lastname: Xi
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
authors.forename: Xinxue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Basic College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D009596:Nitrophenols / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides
keywords: BH3 mimetic; Bcl-2 family; apoptosis; mitochondrial morphology; nutrient starvation