Propranolol attenuates the malignant biological behaviors of renal cancer cells partly through modulation of the IL-6/PI3K/AKT signaling axis.

OBJECTIVE: To investigate the effects of propranolol on the malignant biological behaviours of renal cancer cells and explore the potential involvement of the IL-6/PI3K/AKT signalling axis. METHODS: 786-O and Caki-2 ccRCC cells were treated with gradient propranolol, followed by CCK-8, wound-healing, Transwell and flow cytometry assays to test cell proliferation, migration, invasion and apoptosis. Western blot was applied to measure proteins associated with apoptosis, EMT, IL-6 and PI3K/AKT pathway. A xenograft nude mouse model was constructed to verify propranolol's anti-tumor activity in vivo. RNA-seq combined with GO/KEGG enrichment was used to screen underlying signaling pathways. IL-6 overexpression rescue assays were performed to validate IL-6's functional role in propranolol-mediated phenotypes. RESULTS: Propranolol significantly inhibited the proliferation, migration and invasion of 786-O and Caki-2 cells and induced apoptosis in a concentration-dependent manner. Propranolol upregulated Bax, cleaved-Caspase-3, cleaved-Caspase-9, E-cadherin and TIMP2, while downregulating Bcl-2, N-cadherin, Vimentin and MMP9, suggesting enhanced apoptosis and suppression of EMT- and invasion-related phenotypes. In vivo, propranolol delayed xenograft tumour growth and reduced final tumour volume and weight. RNA-seq identified 984 differentially expressed genes, including 464 upregulated and 520 downregulated genes. Functional enrichment analysis showed that these genes were mainly associated with extracellular matrix remodelling, cytokine activity, hypoxia response, lipid metabolism and tumour-related pathways, including the PI3K/AKT signalling pathway. Western blotting confirmed that propranolol decreased the p-PI3K/PI3K and p-AKT/AKT ratios. In addition, propranolol reduced IL-6 protein expression in renal cancer cells, whereas IL-6 overexpression partially restored propranolol-suppressed cell proliferation, migration and invasion, and partially reversed propranolol-induced changes in apoptosis-related proteins, EMT-related proteins and PI3K/AKT pathway activation. CONCLUSION: Propranolol suppresses the malignant biological behaviours of renal cancer cells and inhibits renal tumour growth in vivo. These effects may be mediated, at least in part, through downregulation of IL-6 and suppression of PI3K/AKT signalling pathway activation.