Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai Key Laboratory of Embryo Original Disease, Shanghai Jiao Tong University, Shanghai, 200025, China.
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Adv Sci (Weinh). 2024 Apr;11(15):e2304203. doi: 10.1002/advs.202304203. Epub 2024 Feb 11.
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.
肿瘤常过度表达葡萄糖调节蛋白，干扰这些蛋白质的产生或活性的药物可能代表新的癌症治疗方法。氯丙嗪衍生物 JX57 对子宫内膜癌具有显著的疗效，且极少出现锥体外系副作用；但其作用机制目前尚不清楚。本研究采用基于活性的蛋白质谱分析和功能丧失实验，鉴定葡萄糖调节蛋白 75kD（GRP75）是 JX57 的直接靶标。研究结果表明，GRP75 是 JX57 发挥生物学活性所必需的，因为 JX57 在体外和体内缺乏 GRP75 的癌细胞中均具有中度的抗癌特性。高 GRP75 表达与子宫内膜癌患者分化不良和生存不良相关，而敲低 GRP75 可显著抑制肿瘤生长。从机制上讲，JX57 与 GRP75 的直接结合会破坏线粒体相关内质网膜的结构，并破坏内质网-线粒体钙稳态，导致线粒体能量危机和 AMP 激活蛋白激酶的激活。综上所述，这些发现表明 GRP75 可作为子宫内膜癌的潜在预后生物标志物和直接治疗靶点，并提示氯丙嗪衍生物 JX57 可能成为子宫内膜癌的一种新的治疗选择。
