Growth inhibition of human hepatocellular carcinoma cells by antagonism of the β(2) adrenergic receptor

Previous studies have shown that the activation of the β(2) adrenergic receptor (ADRB2) can stimulate several signaling pathways that promote tumor growth and metastasis. β-adrenergic antagonism may have a beneficial role in cancer treatment; however, little is known about the effect of ADRB2 inhibition on the growth of human hepatocellular carcinoma (HCC) cells. The present study revealed that ADRB2 was highly expressed in HCC cell lines compared with that in a normal liver cell line. Treatment with the ADRB2 antagonists ICI118,551 and metoprolol significantly inhibited the growth of human HCC cells. Annexin V/propidium iodide apoptosis and Hoechst staining assays revealed that treatment with ADRB2 antagonists induced apoptosis in HCC cells. Additionally, cell cycle analysis using propidium iodide staining demonstrated that growth suppression was associated with G(2)/M phase cell cycle arrest by ADRB2 antagonism in HCC cells. Treatment with the ADRB2 antagonists suppressed HCC growth, possibly through inhibiting expression of B-cell lymphoma-2 (Bcl-2) and upregulating that of caspase-9 and Bcl-2-associated X, as well as downregulating the expression levels of the G(2)/M phase-associated proteins cyclin B1 and cyclin-dependent kinase 1. Therefore, the observations of the present study indicate that ADRB2 blockade inhibited HCC growth, potentially mediated by inducing apoptosis and G(2)/M phase cell cycle arrest. ADRB2 antagonists may therefore be a promising therapeutic strategy for HCC.