MTX-211 Inhibits GSH Synthesis through Keap1/NRF2/GCLM Axis and Exerts Antitumor Effects in Bladder Cancer

Globally, bladder cancer (BLCA) is still the leading cause of death in patients with tumors. The function and underlying mechanism of MTX-211, an EFGR and PI3K kinase inhibitor, have not been elucidated. This study examined the function of MTX-211 in BLCA cells using in vitro and in vivo assays. RNA sequencing, quantitative real-time polymerase chain reaction, Western blotting, co-immunoprecipitation, and immunofluorescence were performed to elucidate the underlying mechanism. Our observations revealed that MTX-211 has a time- and concentration-dependent inhibitory effect on bladder cancer cell proliferation. Flow cytometry analysis showed that cell apoptosis and G0/G1 cell cycle arrest were significantly induced by MTX-211. MTX-211 inhibited intracellular glutathione (GSH) metabolism, leading to a decrease in GSH levels and an increase in reactive oxygen species. GSH supplementation partly reversed the inhibitory effects of MTX-211. Further experiments verified that MTX-211 promoted NFR2 protein ubiquitinated degradation via facilitating the binding of Keap1 and NRF2, subsequently resulting in the downregulated expression of GCLM, which plays a vital role in GSH synthesis. This study provided evidence that MTX-211 effectively inhibited BLCA cell proliferation via depleting GSH levels through Keap1/NRF2/GCLM signaling pathway. Thus, MTX-211 could be a promising therapeutic agent for cancer.

 

Comments:

The study you're describing highlights the potential of MTX-211 as a promising therapeutic agent for bladder cancer. It's fascinating how the compound impacts bladder cancer cells by inhibiting proliferation through various mechanisms.

MTX-211's inhibition of EGFR and PI3K kinase appears to be critical in impeding bladder cancer cell growth, causing both apoptosis and cell cycle arrest. The modulation of intracellular glutathione (GSH) metabolism and subsequent increase in reactive oxygen species (ROS) levels further contribute to its anti-cancer effects.

The specific role of MTX-211 in promoting the degradation of NRF2 via Keap1 interaction is intriguing. By downregulating GCLM expression, which is essential for GSH synthesis, MTX-211 effectively reduces GSH levels, impacting the redox balance and potentially leading to cell death in bladder cancer cells.

This comprehensive understanding of the molecular pathways affected by MTX-211 provides a solid foundation for considering its therapeutic potential in treating bladder cancer. Further research and clinical trials may be warranted to validate these findings and explore the compound's efficacy and safety in human subjects.

The study's insights into the underlying mechanisms of MTX-211 in bladder cancer offer hope for developing more targeted and effective therapies against this challenging disease.

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Related Targets

PI3K EGFR