MTX-211 Inhibits GSH Synthesis through Keap1/NRF2/GCLM Axis and Exerts Antitumor Effects in Bladder Cancer
Bing Hu1,2, Ru Chen1,2, Ming Jiang1,2
1Department of Urology, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang 330006, China.
Abstract:
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.
Insights
MTX-211, an EGFR and PI3K inhibitor, effectively reduces bladder cancer cell proliferation by disrupting glutathione metabolism via the Keap1/NRF2/GCLM pathway. This mechanism leads to increased oxidative stress and cell cycle arrest, suggesting MTX-211 as a potential cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Bladder cancer (BLCA) remains a significant global health challenge with high mortality rates.
- The therapeutic potential and precise mechanisms of MTX-211, an inhibitor targeting EGFR and PI3K, in BLCA are not well understood.
Purpose of the Study:
- To investigate the functional role and underlying molecular mechanisms of MTX-211 in bladder cancer cells.
- To evaluate MTX-211's efficacy in inhibiting BLCA cell proliferation both in vitro and in vivo.
Main Methods:
- Utilized RNA sequencing, qPCR, Western blotting, co-immunoprecipitation, and immunofluorescence assays.
- Performed in vitro and in vivo assays to assess cell proliferation, apoptosis, and cell cycle progression.
- Investigated the impact of MTX-211 on glutathione (GSH) metabolism and reactive oxygen species (ROS) levels.
Main Results:
- MTX-211 demonstrated a time- and concentration-dependent inhibition of BLCA cell proliferation.
- MTX-211 induced significant cell apoptosis and G0/G1 cell cycle arrest.
- MTX-211 depleted intracellular GSH levels, increased ROS, and inhibited the Keap1/NRF2/GCLM pathway, leading to downregulated GCLM expression.
Conclusions:
- MTX-211 inhibits BLCA cell proliferation by depleting GSH levels through the Keap1/NRF2/GCLM signaling pathway.
- MTX-211 promotes NRF2 protein ubiquitinated degradation, impacting GSH synthesis and increasing oxidative stress.
- MTX-211 shows promise as a potential therapeutic agent for bladder cancer treatment.
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