文献类型：期刊文献

英文题名：Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75-IP3R-Ca2+-AMPK Axis

作者：Wang, Qi[1,2];Li, Lijuan[1];Gao, Xiaoyan[1];Zhang, Chunxue[1];Xu, Chen[1];Song, Lingyi[2];Li, Jian[2];Sun, Xiao[1];Mao, Fei[2];Wang, Yudong[1]

机构：[1]Shanghai Jiao Tong Univ, Shanghai Key Lab Embryo Original Dis, Female Tumor Reprod Specialty, Int Peace Matern & Child Hlth Hosp,Sch Med,Dept Gy, Shanghai 200025, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Frontiers Sci Ctr Materiobiol & Dynam Chem, Shanghai Key Lab New Drug Design,Sch Pharm,State K, Shanghai 200237, Peoples R China

年份：2024

卷号：11

期号：15

外文期刊名：ADVANCED SCIENCE

收录：;EI(收录号：20240715536058);WOS:【SCI-EXPANDED(收录号:WOS:001160977000001)】；

基金：The present work was supported by the Program of Shanghai Academic Research Leader (No. 22XD1403500), the Central Guidance on Local Science and Technology Development Fund of Shanghai Province (No. YDZX20223100003006), the Shanghai Municipal Key Clinical Specialty (No. shslczdzk06302), the "Science and Technology Innovation Action Plan" International Science and Technology Cooperation Project (No. 20550760600), the Shanghai Shenkang Hospital Development Center Clinical Technology Innovation Project (No. SHDC12020130), and the Shanghai Jiao Tong University Medicine-Engineering Fund (No. YG2022ZD).

语种：英文

外文关键词：chlorpromazine; endometrial cancer; GRP75; MAM

摘要：Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose-regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity-based protein profiling and loss-of-function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75-deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria-associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum-mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP-activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer.