HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells  

作　　者：Xinxin Kou Xiaoxia Yang Zheng Zhao Lei Li 

机构地区：[1]Department of Gynecology,Cancer Hospital Affiliated to Zhengzhou University,Zhengzhou 450008,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第3期356-365,共10页生物化学与生物物理学报（英文版）

基　　金：This work was supported by the grant from the construction Joint Project of Henan Province Medical Science and Technology Research Plan in 2022(No.LHGJ20220200).

摘　　要：Currently,platinum agents remain the mainstay of chemotherapy for ovarian cancer(OC).However,cisplatin(DDP)resistance is a major reason for chemotherapy failure.Thus,it is extremely important to elucidate the mechanism of resistance to DDP.Here,we establish two DDP-resistant ovarian cancer cell lines and find that caseinolytic protease P(CLPP)level is significantly downregulated in DDP-resistant cell lines compared to wild-type ovarian cancer cell lines(SK-OV-3 and OVcar3).Next,we investigate the functions of CLPP in DDP-resistant and wild-type ovarian cancer cells using various assays,including cell counting kit-8 assay,western blot analysis,immunofluorescence staining,and detection of reactive oxygen species(ROS)and apoptosis.Our results show that CLPP knockdown significantly increases the half maximal inhibitory concentration(IC_(50))and mitophagy of wild-type SK-OV-3 and OVcar3 cells,while CLPP overexpression reduces the IC_(50) values and mitophagy of DDP-resistant SK-OV-3 and OVcar3 cells.Next,we perform database predictions and confirmation experiments,which show that heat shock protein family A member 8(HSPA8)regulates CLPP protein stability.The dynamic effects of the HSPA8/CLPP axis in ovarian cancer cells are also examined.HSPA8 increases mitophagy and the IC_(50) values of SK-OV-3 and OVcar3 cells but inhibits their ROS production and apoptosis.In addition,CLPP partly reverses the effects induced by HSPA8 in SK-OV-3 and OVcar3 cells.In conclusion,CLPP increases DDP resistance in ovarian cancer by inhibiting mitophagy and promoting cellular stress.Meanwhile,HSPA8 promotes the degradation of CLPP protein by regulating its stability.

关 键 词：cisplatin resistance ovarian cancer caseinolytic protease P heat shock protein family A member 8 MITOPHAGY 

分 类 号：R737.31[医药卫生—肿瘤]