Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin

by Selleckchem | Oct 06 2023

Glutathione peroxidase 4 (GPX4) has been confirmed to inhibit ferroptosis in cancer cells, however, whether GPX4 serves as an oncogene is not clear. In this study, the expression of GPX4 and its influence to survival of patients with cancer were analyzed via public databases. Furthermore, the epigenetic regulation of GPX4 and the relation between GPX4 and chemoresistance of different anticancer drugs was also detected. Most importantly, cytological assays were performed to investigate the function of GPX4 in cancer cells. The results showed that GPX4 was higher expressed in cancer tissues than normal and was negatively associated with prognosis of patients. Furthermore, at upstream of GPX4 there was low DNA methylation sites and enhanced level of H3K4me3 and H3K27ac, indicating that high level of GPX4 in cancer may resulted from epigenetic regulation. Moreover, GPX4 was positively related to chemoresistance of anticancer drugs L-685458, lapatinib, palbociclib, and topotecan. In addition, GPX4 may potentially be involved in translation of protein, mitochondrial respiratory chain complex I assembly, electron transport oxidative phosphorylation, nonalcoholic fatty liver disease, and metabolic pathways. Finally, we detected that GPX4 inhibited ferroptosis in cancer cells, the inhibition of GPX4 via RSL3 could enhance the anticancer effect of cisplatin in vitro and in vivo. In conclusion, GPX4 acts as an oncogene and inhibits ferroptosis in cancer cells, the anticancer effect of cisplatin can be enhanced by GPX4 inhibition.

Comments:

The study you described focused on investigating the role of glutathione peroxidase 4 (GPX4) in cancer cells. GPX4 is known to inhibit a form of cell death called ferroptosis. However, the study aimed to determine whether GPX4 itself acts as an oncogene, a gene that promotes cancer development. The researchers analyzed the expression of GPX4 in cancer tissues and its impact on patient survival using publicly available databases.

The results of the study showed that GPX4 was more highly expressed in cancer tissues compared to normal tissues. Furthermore, high expression of GPX4 was negatively associated with the prognosis of cancer patients, suggesting that GPX4 may play a role in cancer progression.

The researchers also investigated the epigenetic regulation of GPX4, which refers to modifications in the DNA and proteins associated with the DNA that can influence gene expression. They found that upstream of the GPX4 gene, there were regions with low DNA methylation (a type of epigenetic modification) and increased levels of certain histone modifications, specifically H3K4me3 and H3K27ac. This suggests that the high expression of GPX4 in cancer cells may be the result of epigenetic regulation.

Additionally, the study examined the relationship between GPX4 and the resistance of cancer cells to various anticancer drugs. The results showed a positive correlation between GPX4 expression and resistance to L-685458, lapatinib, palbociclib, and topotecan, suggesting that GPX4 may contribute to chemoresistance in cancer.

Furthermore, the study explored the potential biological functions of GPX4. The analysis indicated that GPX4 may be involved in various cellular processes, including protein translation, assembly of mitochondrial respiratory chain complex I, electron transport oxidative phosphorylation, nonalcoholic fatty liver disease, and metabolic pathways. These findings suggest that GPX4 may have broader implications beyond its role in ferroptosis inhibition.

Finally, the researchers performed cytological assays to investigate the functional impact of GPX4 in cancer cells. The results demonstrated that GPX4 indeed inhibited ferroptosis in cancer cells. Moreover, they found that inhibiting GPX4 using a compound called RSL3 could enhance the anticancer effect of cisplatin, both in vitro (in cell cultures) and in vivo (in animal models).

In conclusion, this study provides evidence that GPX4 acts as an oncogene and inhibits ferroptosis in cancer cells. The findings suggest that targeting GPX4 could enhance the effectiveness of cisplatin as an anticancer treatment.