The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells

Increasing data indicate that stress hormones and their corresponding receptors play an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). However, there is presently no study investigating the influence of stress hormones in correlation with β-AR on human HCC cells. We examined the expression of α1- and β-ARs in human HCC cell line HepG2 and MHCC97H cells in comparison with that in human normal hepatic cell line HL-7702 cells (L-02), and the influence of isoproterenol (ISO) on the growth of these HCC cells using blocking agents in correlation with β-AR and its downstream signaling pathways. We found that α1-AR was down-regulated and β-AR was up-regulated in HepG2 and MHCC97H cells. ISO dose-dependently promoted the growth of both HepG2 and MHCC97H cells. ISO-induced growth and survival of HCC cells were effectively attenuated by ICI 118551, U0126 and PD153035, but not by H-89 or LY294002. ISO transiently activated MAPK/ERK1/2 in tumor cells which could be blocked either by ICI 118551 or U0126, but not by H-89, LY294002, or PD153035. These findings indicate that ISO mimicking a mitogen promoted the growth of HepG2 and MHCC97H cells via β-AR-mediated activation of both MAPK/ERK1/2 dependent and independent signaling pathways, and ISO activated MAPK/ERK1/2 by an EGFRindependent mechanism.