Ethacrynic acid inhibits the growth and proliferation of prostate cancer cells by targeting GSTP1 and regulating the PI3K-AKT signaling pathway

Abstract

Background

As a diuretic, ethacrynic acid (EA) has been shown to play a suppressive role in cancers, including prostate cancer (PC). However, its molecular regulatory mechanism is still unclear. Therefore, our study is centered on investigating the effect of EA on PC development and its mechanism.

Methods

To verify the binding relationship between EA and GSTP1, molecular docking and cellular thermal shift assay (CETSA) were conducted. To examine how EA affects PC cell proliferation, cell cycle, and apoptosis, cell function assays were performed. qRT-PCR was used to detect GSTP1 mRNA expression. The expression of GSTP1 protein and PI3K-AKT signaling pathway-related proteins in cells was detected by western blot (WB). To verify how EA and GSTP1 influence cell growth in PC, in vivo experiments were conducted.

Results

The binding relationship between GSTP1 and EA was confirmed by molecular docking and CETSA results. Cell experiments showed that EA could hinder PI3K/AKT pathway and PC cell proliferation, arrest the cell cycle in G0/G1 phase, and facilitate apoptosis by binding to GSTP1. In vivo experiments in nude mice verified that the interaction between EA and GSTP1 reduced PI3K and AKT phosphorylation and inhibited the growth of PC cells.

Conclusion

EA inhibits PC progression by binding to GSTP1 to downregulate the activity of PI3K/AKT pathway, and this result suggests the potential of EA to be an anticancer agent for PC therapy.