Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors

	Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors
	Chen, Hua-Dong 1,2; Guo, Ne 1,2; Song, Shan-Shan 1,2; Chen, Chuan-Huizi 1,2; Miao, Ze-Hong 1,2,3; He, Jin-Xue 1,2
刊名	AMERICAN JOURNAL OF CANCER RESEARCH
	2020
卷号	10 期号:9 页码:2813-+
关键词	PARP inhibitors resistance BRCA2 COX-2 BIRC3 apoptotic resistance
ISSN号	2156-6976
通讯作者	Miao, Ze-Hong(zhmiao@simm.ac.cn) ; He, Jin-Xue(jinxue_he@simm.ac.cn)
英文摘要	Several poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) have been approved for cancer therapy; however, intrinsic and acquired resistance has limited their efficacy in the clinic. In fact, cancer cells have developed multiple mechanisms to overcome PARPi cytotoxicity in even a single cancer cell. In this study, we generated three PARPi-resistant BRCA2-deficient pancreatic Capan-1 variant cells using olaparib (Capan-1/OP), talazoparib (Capan-1/TP), and simmiparib (Capan-1/SP). We identified novel mutations in intron 11 of BRCA2, which resulted in the expression of truncated BRCA2 splice isoforms. Functional studies revealed that only a fraction (32-49%) of PARPi sensitivity could be rescued by depletion of BRCA2 isoforms. In addition, the apoptosis signals (phosphatidylserine eversion, caspase 3/7/8/9 activation, and mitochondrial membrane potential loss) were almost completely abrogated in all PARPi-resistant variants. Consistently, overexpression of the anti-apoptotic proteins cyclooxygenase 2 (COX-2) and baculoviral IAP repeat-containing 3 (BIRC3) occurred in these variants. Depletion of COX-2 or BIRC3 significantly reduced apoptotic resistance in the PARPi-resistant sublines and reversed PARPi resistance by up to 70-72%. Furthermore, exogenous addition of prostaglandin E2, a major metabolic product of COX-2, inhibited PARPi-induced apoptotic signals; however, when combined with the BIRC3 inhibitor LCL161, there was significantly enhanced sensitivity of the resistant variants to PARPi. Finally, PARPi treatment or PARP1 depletion led to a marked increase in the mRNA and protein levels of COX-2 and BIRC3, indicating that PARP1 is a negative transcriptional regulator of these proteins. Together, our findings demonstrated that during the chronic treatment of cells with a PARPi, both BRCA2 intron 11 mutations and COX-2/BIRC3-mediated apoptotic resistance led to PARPi resistance in pancreatic Capan-1 cells.
资助项目	National Natural Science Foundation of China[81573450] ; National Natural Science Foundation of China[81603160] ; National Natural Science Foundation of China[81773764] ; Chinese Academy of Sciences[29201731121100101] ; Chinese Academy of Sciences[XDA12010306] ; Chinese Academy of Sciences[XDA-12020104] ; Chinese Academy of Sciences[XDA12020109] ; Chinese Academy of Sciences[CASIMM0120185003] ; Science and Technology Commission of Shanghai Municipality[19QA1410900] ; Science and Technology Commission of Shanghai Municipality[16JC1406300] ; State Key Laboratory of Drug Research ; Open Studio for Drugability Research of Marine Natural Products in the Qingdao Pilot National Laboratory for Marine Science and Technology ; SA-SIBS Scholarship Program
WOS关键词	ACQUIRED-RESISTANCE ; INDUCED APOPTOSIS ; ANTICANCER ACTIVITY ; MYELOID-LEUKEMIA ; DNA-DAMAGE ; CELLS ; THERAPY ; MECHANISM ; RUCAPARIB ; PATHWAYS
WOS研究方向	Oncology
语种	英语
出版者	E-CENTURY PUBLISHING CORP
WOS记录号	WOS:000579459200009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291518]
专题	中国科学院上海药物研究所
通讯作者	Miao, Ze-Hong; He, Jin-Xue
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Drugabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China
推荐引用方式 GB/T 7714	Chen, Hua-Dong,Guo, Ne,Song, Shan-Shan,et al. Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors[J]. AMERICAN JOURNAL OF CANCER RESEARCH,2020,10(9):2813-+.
APA	Chen, Hua-Dong,Guo, Ne,Song, Shan-Shan,Chen, Chuan-Huizi,Miao, Ze-Hong,&He, Jin-Xue.(2020).Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors.AMERICAN JOURNAL OF CANCER RESEARCH,10(9),2813-+.
MLA	Chen, Hua-Dong,et al."Novel mutations in BRCA2 intron 11 and overexpression of COX-2 and BIRC3 mediate cellular resistance to PARP inhibitors".AMERICAN JOURNAL OF CANCER RESEARCH 10.9(2020):2813-+.