二甲双胍增强癌细胞对化疗敏感性

Chemotherapy resistance is a major obstacle to cure of endometrial cancer. Previous studies have shown that the diabetes treatment drug metformin can enhance the sensitivity of endometrial cancer to chemotherapy drugs. Some recent studies have shown that isocitrate dehydrogenase 1 (IDH1) is involved in cancer chemotherapy resistance, and epigenetic modifications can also promote chemotherapy resistance. However, it is not completely clear whether IDH1 is involved in metformin-induced chemotherapy sensitivity of endometrial cancer through epigenetic modification. Recently, researchers at the University of Texas Southwestern Medical Center conducted an in-depth study on the above issues.

The researchers evaluated the expression of IDH1 in endometrial tissue and serum through immunohistochemistry and Elisa experiments, used Western blot to detect the expression changes of key molecules in the IDH1-α-KG-TET1-Nrf2 signaling pathway under different treatments, used Dot blot experiments to evaluate the overall hydroxymethylation level after metformin treatment or plasmid transfection, and used reporter gene experiments to detect the antioxidant response element (antioxidant response) in the IDH1 promoter region. element) activity, the sensitivity of cancer cells to chemotherapy drugs was detected through SRB experiments.

After a series of experimental analyses, the researchers found that the abnormal expression of IDH1 and its downstream mediators led to the activation of the IDH1 signaling pathway in endometrial cancer tissue, causing cancer cells to become resistant to chemotherapy. Metformin treatment could eliminate this effect. Dot blot and HMeDIP experiments revealed that metformin can block the enhancement of Nrf2 hydroxymethylation modification levels mediated by IDH1-α-KG-TET1 and eliminate chemotherapy resistance. The researchers further observed that Nrf2 can bind to the antioxidant response element in the IDH1 promoter region and activate the IDH1-α-KG-TET1-Nrf2 regulatory circuit to enhance the chemotherapy resistance of cancer cells.

In summary, this study shows that the IDH1-α-KG-TET1-Nrf2 signaling pathway plays an important role in the chemotherapy resistance of cancer cells, suggesting that the rational combination of metformin and chemotherapy drugs is expected to solve the problem of chemotherapy resistance.

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