Inhibition of the PI3K/AKT signaling pathway contributes to the anti-renal cell carcinoma effects of deoxyelephantopin

Abstract

Renal cell carcinoma (RCC) is the most common kidney cancer. Despite advances in treatment, current therapeutic strategies are often limited by side effects, drug resistance, and low response rates, necessitating alternatives for RCC treatment. Deoxyelephantopin (DEO), a sesquiterpene lactone from Elephantopi Herba, has demonstrated anticancer properties in multiple cancer models; however, its effects on RCC remain unknown. This study aimed to investigate the anti-RCC effects of DEO and its underlying molecular mechanisms. Human RCC cell lines (786-O, Caki-1, A498) and a murine RCC cell line (RENCA) were used for in vitro assays. Results revealed that DEO dose-dependently inhibited cell viability and colony formation in 786-O, Caki-1, A498, and RENCA cells, while also inducing apoptosis in 786-O and Caki-1 cells. A RENCA allograft mouse model was used for in vivo assays. DEO significantly suppressed tumor growth without causing notable changes in body weight, organ coefficients, or serum biochemical markers (ALT, AST, BUN, Cr). Network pharmacology analysis predicted the PI3K/AKT signaling pathway as a key mediator of DEO's anti-RCC effects. Western blotting showed that DEO downregulated the expression of EGFR, p-EGFR (Tyr1068), PI3K p110α, p-Akt (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), 4E-BP1, p-4E-BP1 (Thr37/46), HIF-1α, and Bcl-2. Overactivation of AKT attenuated DEO's inhibitory effects on cell viability in 786-O cells. In conclusion, this study is the first to demonstrate that DEO exerts anti-RCC effects in both cellular and animal models, primarily through inhibition of the PI3K/AKT pathway. These findings suggest that DEO holds promise as a lead compound for RCC management.