Multiple anticancer effects of blocking MEK-ERK signaling in hepatocellular carcinoma

BACKGROUND: Human hepatocellular carcinoma (HCC) is associated with increased expression and activity of mitogen-activated protein kinase (MAPK) signaling intermediates (ie, MEK, ERK). STUDY DESIGN: We determined the effects of MEK-ERK signaling on proliferation, cell cycle, apoptosis, and tumorigenicity of HCC in vitro. HCC cell lines were treated with MEK enzyme-specific inhibitors, PD098059 and U0126, and ERK1,2 oligonucleotide antisense. RESULTS: In the HCC cells examined, MEK inhibitors blocked ERK1,2 phosphorylation without a change in total ERK expression. ERK1,2 oligonucleotide antisense inhibited ERK1,2 protein expression. PD098059, U0126, and ERK1,2 oligonucleotide antisense each inhibited HCC cellular proliferation in a concentration-dependent manner. Cell cycle, apoptosis, and tumorigenicity were examined in Hep3B and HepG2 cell lines. MEK enzyme inhibition resulted in anticancer effects through cell cycle arrest, increased apoptosis, and decreased tumorigenicity in these cell lines. U0126 exhibited more potent inhibition of ERK1,2 phosphorylation and had more pronounced anticancer effects in both cell lines. Correspondingly, HepG2 cells, the cell line more sensitive to ERK1,2 phosphorylation inhibition, sustained more pronounced anticancer effects with treatment. But Hep3B cells were more sensitive to ERK1,2 antisense-mediated decreases in ERK1,2 protein expression and correspondingly, their growth was inhibited to a greater degree than the HepG2 cells. MEK enzyme inhibition had downstream effects on the expression of the antiapoptotic protein survivin in both cell lines. CONCLUSIONS: These data suggest that there are multiple anticancer effects of blocking MEK-ERK signaling, and that these depend on both the susceptibility of the cells and the ability of the treatment to effect a selective block of MEK-ERK signaling in HCC cells. (C) 2004 by the American College of Surgeons.