Salidroside overcomes cisplatin resistance in ovarian cancer via the inhibition of CRNDE-mediated autophagy

Cisplatin (DDP) resistance significantly affects the survival rate of patients with ovarian Cancer (OC). Autophagy is recognized as a common cause of resistance to DDP. This study aimed to investigate the impact of salidroside on OC progression and explore its potential regulatory effects on DDP resistance and Autophagy. A DDP-resistant A2780 (A2780/DDP) cell line was induced by exposure to increasing DDP concentrations. The protein levels of Autophagy proteins (p62, Beclin-1, ATG5, and LC3 II/LC3 I), Apoptosis proteins (cleaved Caspase-3 and cleaved caspase-9), and PI3K/Akt/mTOR pathway were determined by western blotting. Autophagic vacuoles in cells were observed with LC3 dyeing with confocal fluorescent microscopy. Cell viability and Apoptosis were evaluated by cell counting kit-8 assays and flow cytometry. RT-qPCR was conducted to measure the relative levels of various lncRNAs in A2780 or A2780/DDP cells. A xenograft model was established by subcutaneous injection of 1 × 10⁷ A2780 cells into the posterior flank of nude mice. Tumor size and weight were recorded. The expression of Ki67, cleaved Caspase-3 and LC3 in tumor tissues was assessed by immunohistochemistry staining. The biodistribution of DDP in organs and blood of normal nude mice and tumors of tumor-bearing mice was detected using the ICP-MS. Hematoxylin-eosin staining was used to assess the histopathological changes of kidney, liver, and spleen sections. For in vitro analysis, Autophagy was enhanced in DDP-resistant A2780 cells. Additionally, salidroside inhibits DDP resistance to A2780 cells via Autophagy inhibition. Mechanistically, salidroside downregulated CRNDE in DDP-resistant A2780 cells. CRNDE knockdown inhibited Autophagy, while CRNDE overexpression reversed the protective effects of salidroside. Additionally, salidroside activated the PI3K/Akt/mTOR pathway in DDP-resistant A2780 cells, and inhibition of PI3K reversed the effect of salidroside on inhibiting Autophagy and Apoptosis of A2780/DDP cells. For in vivo analysis, salidroside inhibited tumor growth, Autophagy, and nephrotoxicity of DDP. Additionally, salidroside downregulated CRNDE and activated PI3K/Akt/mTOR signaling in vivo. Salidroside prevents autophagy-mediated DDP resistance in OC by downregulating lncRNA CRNDE and activating the PI3K/Akt/mTOR pathway.

Autophagy; CRNDE; Cisplatin; Ovarian cancer; Resistance; Salidroside.