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Addiction to protein kinase Cɩdue to PRKCI gene amplification can be exploited for an aptamer-based targeted therapy in ovarian cancer

引用

Signal Transduction and Targeted Therapy 2020年第1期5卷 1080-1090页

作者： hina rehmani Yue Li Tao Li Ravi Padia Ozlem Calbay Lingtao Jin Huijun Chen Shuang Huang Department of Biochemistry and Cancer Biology Medical College of GeorgiaAugusta UniversityAugustaGA 30912USA Department of Anatomy and Cell Biology University of Florida College of MedicineGainesvilleFL 32610USA Department of Gynecology and Obstetrics Zhongnan Hospital of Wuhan University430071 WuhanHubeiChina

PRKCI,the gene for protein kinase Cι(PKCι),is frequently amplified in ovarian cancer and recent studies have shown that PKCιparticipates in ovary ***,it is unknown whether PKCιis differentially involved in the growth/survival between PRKCI-amplified and non-amplified ovarian cancer *** this study,we analyzed ovarian cancer patient dataset and revealed that PRKCI is the only PKC family member significantly amplified in ovarian cancer and PRKCI amplification is associated with higher PKCι*** a panel of ovarian cancer cell lines,we found that abundance of PKCιis generally associated with PRKCI ***,silencing PKCιled to apoptosis in PRKCI-amplified ovarian cancer cells but not in those without PRKCI amplification,thus indicating an oncogenic addiction to PKCɩin PRKCI-amplified *** small-molecule inhibitors characterized to selectively block atypical PKCs did not offer selectivity nor sensitivity in PRKCI-amplified ovarian cancer cells and were even cytotoxic to non-cancerous ovary surface or fallopian tube epithelial cells,we designed an EpCAM aptamer-PKCιsiRNA chimera(EpCAM-siPKCιaptamer).EpCAM-siPKCιaptamer not only effectively induced apoptosis of PRKCI-amplified ovarian cancer cells but also greatly deterred intraperitoneal tumor development in xenograft mouse *** study has demonstrated a precision medicine-based strategy to target a subset of ovarian cancer that contains PRKCI amplification and shown that the EpCAM aptamerdelivered PKCιsiRNA may be used to suppress such tumors.

关键词： expression cancer PRK

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