Embelin Enhances the Sensitivity of Renal Cancer Cells to Axitinib by Inhibiting HIF Signaling Pathway

Background: Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system with a high recurrence rate and easy metastasis. Current clinical drugs for renal cell carcinoma include immunotherapies and targeted drugs. Axitinib is a clinically targeted drug for treating renal cell carcinoma, which has shortcomings such as unstable efficacy and easy drug resistance. Therefore, this study aims to determine whether embelin can enhance the sensitivity of renal cancer cells to axitinib and explore its regulatory pathways. Methods: The enhancing effect of embelin on axitinib was detected using MTT, crystal violet staining, and annexin VFITC staining in two renal cancer cell lines. Western blot was performed to detect the expression of autophagy-related proteins under different conditions. Bioinformatic tools were used to predict the pathways through which embelin may act on renal cancer cells, and pharmacological methods were used to verify the results. Results: Embelin enhanced the sensitivity of renal cancer cells to axitinib in the following aspects: enhancing the inhibition of cell proliferation by axitinib, and the induction of cell apoptosis. HIF was a potential pathway for embelin’s action. After IOX2 regulated the HIF-1α pathway, the enhancing effect of embelin on axitinib was weakened. Moreover, after PT2977 regulated the HIF-2α pathway, the enhancing effect of embelin on axitinib was weakened. Conclusions: Embelin enhanced the sensitivity of A498 and 786-O renal cancer cells to axitinib by inhibiting the HIF pathway.