Therapeutic Strategies for Hepatocellular Carcinoma Based on Analyses for Resistance to Apoptosis Mediated by Activation of Intracellular Signal Pathways

Abstract

Evidence clearly demonstrates that transforming hepatocytes are gaining phenotypes, either accelerating cell cycles or resisting apoptosis, during hepatocarcinogenesis. Disorder of intracellular signaling seems to be closely related to the acquisition of such malignant phenotypes. Thus it is important to understand how the intracellular signaling is constitutively activated or improperly regulated. It is beneficial to clarify these pathways for the sake of preparing new therapeutic strategies against human hepatocellular carcinoma (HCC). On the other hand, insulin is a hepatotrophic factor that stimulates growth of normal hepatocytes and HCC-derived cell lines. The insulin receptor substrate-1 protein (IRS-1) is a specific substrate for insulin receptor tyrosine kinase. Expression and tyrosyl phosphorylation of IRS-1 plays an important role during normal hepatocyte growth, and the gene is overexpressed in HCC tissue. Previously, we reported that IRS-1 could induce cellular transformation similar to a dominant oncogene. Interestingly, it has been reported that several cytokines, such as insulin and insulin-like growth factors, could inhibit apoptotic phenomena. Here we reviewed the role of IRS-1 overexpression in hepatic carcinogenesis from the viewpoint of transforming activities and acquisition of resistance to apoptosis. These analyses may permit a new understanding of oncogenes, by which overexpression cells could acquire not only the transforming phenotype but also the ability to escape from programmed cell death, thereby becoming resistant to therapy. Moreover, they may lead to new therapeutic strategies for HCC, targeting the intracellular signaling molecules.