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Published on: July 25, 2020
Targeting GRP75 with a Chlorpromazine Derivative Inhibits Endometrial Cancer Progression Through GRP75-IP3R-Ca2+-AMPK
Qi Wang1,2, Lijuan Li1, Xiaoyan Gao1
1Department 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.
Abstract:
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.
Insights
The study identifies glucose-regulated protein 75 kD (GRP75) as a direct target of the drug JX57. Inhibiting GRP75 shows potential for treating endometrial cancer by disrupting cell energy and calcium balance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tumors frequently overexpress glucose-regulated proteins, suggesting their potential as therapeutic targets.
- JX57, a chlorpromazine derivative, shows promise against endometrial cancer but its mechanism is unclear.
Purpose of the Study:
- To identify the direct molecular target of JX57.
- To elucidate the mechanism by which JX57 exerts its anticancer effects.
- To evaluate GRP75 as a prognostic biomarker and therapeutic target in endometrial cancer.
Main Methods:
- Activity-based protein profiling to identify JX57 targets.
- Loss-of-function experiments to assess GRP75's role in JX57 activity.
- In vitro and in vivo studies using GRP75-deficient cancer cells.
- Analysis of GRP75 expression correlation with patient survival and tumor differentiation.
Main Results:
- Glucose-regulated protein 75 kD (GRP75) was identified as a direct target of JX57.
- JX57's anticancer efficacy is dependent on GRP75; it is reduced in GRP75-deficient cells.
- High GRP75 expression correlates with poor differentiation and survival in endometrial cancer patients.
- JX57 binding to GRP75 disrupts mitochondrial-ER membrane structure, calcium homeostasis, and energy metabolism, activating AMPK.
Conclusions:
- GRP75 is essential for JX57's anticancer activity and is a direct therapeutic target.
- GRP75 serves as a potential prognostic biomarker for endometrial cancer.
- JX57 represents a potential novel therapeutic agent for endometrial cancer.
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