Cuproptosis is a newly defined regulated cell death model and is considered as a potential approach for cancer treatment. We have previously found that cervical cancer cells have the capability of anti-ferroptosis. A recent study has reported that elesclomol (ES) is able to induce copper-dependent ferroptosis. However, its effect on cervical cancer cell ferroptosis is still unclear. In this study, we found that the expression levels of copper metabolism-related genes ATP7A and ATP7B were decreased in cervical cancer tissues. In cervical cancer cells, combined treatment of ES and Cu2+ inhibited cell proliferation and promoted cell death, but did not promote cuproptosis. However, ES-Cu2+ treatment led to the accumulation of cellular reactive oxygen species, increased cellular Fe2+ levels, and decreased expression of GPX4. Moreover, the expression levels of HMOX1 and FTH1 were increased, while the expression level of TFRC was decreased after co-treated with ES-Cu2+ in cervical cancer cells. The decreased expression of GPX4 induced by ES-Cu2+ was attenuated by ferroptosis inhibitors ferrostatin-1 and DFO. Knockdown of HMOX1 could alleviate ES-Cu2+-induced GPX4 downregulation. The expression level of HMOX1 was upregulated in cervical cancer tissues and was negatively associated with ATP7B. In conclusion, copper metabolism is altered in cervical cancer tissues. ES-Cu2+ co-treatment induce ferroptosis in cervical cancer cells by upregulating HMOX1. Our study provides new insights into the relation between cuproptosis and ferroptosis, which may be potential for clinical therapies of cervical cancer.
Zhao et al. (Thu,) studied this question.