期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 96, 期 -, 页码 22-29出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2017.09.111
关键词
Ovarian cancer; Cisplatin resistance; Mitochondrial fission; Apoptosis; Mitophagy; ABT737
资金
- National Nature and Science Foundation of China [NSFC 81372793, 81100808]
- Department of Education of Jilin Province Project [2016237]
The anti-apoptotic BCL2 family of proteins elicits a broad cell survival program mainly by promoting cell migration, invasion, and metastasis. High expression level of BCL2 family proteins is a characteristic feature of cancer cells, especially in cisplatin-resistant cancer cells. Recent studies have shown that BCL2 family proteins play a housekeeping role in modulating mitochondrial dynamics. However, it is not clear whether BCL2 family proteins are relevant to mitochondrial fission and fusion in cisplatin-resistant ovarian cancer cells. Here, we report that the BCL2/BCLXL inhibitor ABT737 induced apoptosis more potently in cisplatin-resistant SKOV3/DDP ovarian cancer cells than in cisplatin-sensitive SKOV3 ovarian cancer cells. ABT737 significantly increased levels of DRP1 in mitochondria and increased rates of mitochondrial fission, and then induced cytochrome C release from mitochondria and mitophagy in SKOV3/DDP cells. Mdivi-1, a selective inhibitor of DRP1, weakened ABT737-induced mitochondrial fission, intrinsic apoptotic pathways, and mitophagy in SKOV3/DDP cells. Taken together, these results demonstrate a novel function of ABT737 in inducing DRP1-dependent apoptotic mitochondrial fission and highlight that targeting anti-apoptotic BCL2 family proteins may be an emerging therapeutic strategy for patients with cisplatin-resistant ovarian cancer.
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