4.1 Article

Silencing TRPM2 enhanced erastin- and RSL3-induced ferroptosis in gastric cancer cells through destabilizing HIF-1α and Nrf2 proteins

期刊

CYTOTECHNOLOGY
卷 74, 期 5, 页码 559-577

出版社

SPRINGER
DOI: 10.1007/s10616-022-00545-z

关键词

TRPM2; Ferroptosis; Gastric cancer; HIF-1 alpha; Nrf2

资金

  1. Shaoguan Science and Technology Project [200812114531705]
  2. Shaoguan Health Research Project [Y20204]

向作者/读者索取更多资源

TRPM2 plays a crucial role in promoting cancer cell survival and is associated with ferroptosis. Silencing TRPM2 enhances the sensitivity of gastric cancer cells to Erastin and RSL3-induced ferroptosis.
Ferroptosis is a regulated form of cell death driven by small molecules or conditions that induce lipid-based reactive oxygen species (ROS) accumulation. Cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival. Our bioinformatic analysis revealed that TRPM2 is associated with cellular responses to chemical stimulus and oxidative stress, implying the potential role of TRPM2 in ferroptosis. Gastric cancer cells were treated with the ferroptosis-inducer, Erastin and RSL3. siRNA transfection was used to silence TRPM2. The levels of GSH, Fe2+, ROS and lipid peroxidation, and the activity of GPx activity were evaluated by flow cytometry and spectrophotometer. The effect of TRPM2 on ubiquitination of HIF-1 alpha and Nrf2 were evaluated by co-immunoprecipitation. Erastin and RSL3 induced the up-regulation of TRPM2 in gastric cancer cell lines, especially in SGC7901 and MGC803. These two cells also showed stronger resistance to Erastin and RSL3 than the other cell lines. TRPM2 knockdown reduced the concentration of GSH and GPx activity, but enhanced the concentration of Fe2+, ROS and lipid peroxidation, which are significant indicators of ferroptosis. Importantly, silencing TRPM2 enhanced the inhibitory effects of Erastin and RSL3 on gastric cancer cell viability, migration, and invasion. TRPM2 stabilized and finally elevated the abundance of HIF-1 alpha and Nrf2 in SGC7901 and MGC803 cells upon Erastin and RSL3. Activation of HIF-1 alpha impaired Erastinand RSL3-induced ferroptosis after TRPM2 knockdown. Collectively, silencing TRPM2 enhanced Erastin- and RSL3-induced ferroptosis in gastric cancer cells through destabilizing HIF-1 alpha and Nrf2 proteins.

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