Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis

Background Bladder cancer is the most common malignant tumor of the urinary system. Surgical resection and chemotherapy are the two mainstream treatments for bladder cancer. However, the outcomes are not satisfactory for patients with advanced bladder cancer. There is a need to further explore more effective targeted therapeutic strategies. Methods Proteomics were performed to compare protein expression differences between human bladder cancer tissues and adjacent normal tissues. The function of GPD1 on bladder cancer cells were confirmed through in vivo and in vitro assays. Transcriptomics and metabolomics were performed to reveal the underlying mechanisms of GPD1. Virtual screening was used to identify allosteric activator of GPD1. Results Here, we used proteomics to find that GPD1 expression was at low levels in bladder cancer tissues. Further investigation showed that GPD1 overexpression significantly promoted apoptosis in bladder cancer cells. Based on transcriptomics and metabolomics, GPD1 promotes Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. Finally, we performed a virtual screening to obtain the GPD1 allosteric activator wedelolactone and demonstrated its ability to inhibit bladder tumor growth in vitro and in vivo. Conclusions This study suggests that GPD1 may act as a novel tumor suppressor in bladder cancer. Pharmacological activation of GPD1 is a potential therapeutic approach for bladder cancer.

Automated summary

This study found that GPD1 was expressed at low levels in bladder cancer tissues and promoted apoptosis in bladder cancer cells. GPD1 was shown to regulate Ca2+ influx and apoptosis of tumor cells via the lysoPC-PAFR-TRPV2 axis. The GPD1 allosteric activator, wedelolactone, inhibited bladder tumor growth in vitro and in vivo. Pharmacological activation of GPD1 may be a potential therapeutic approach for bladder cancer.