Transforming growth factor-α inhibits the intrinsic pathway of c-myc-induced apoptosis through activation of nuclear factor-κB in murine hepatocellular carcinomas

Nuclear factor-kappa B (NF-kappa B) plays an important role during liver neoplastic development through transcriptional regulation of prosurvival genes, which then counteract the death-inducing signals elicited by the host immune response. The c-Myc proto-oncogene is frequently deregulated in liver tumors. Furthermore, enforced expression of c-Myc in the liver promotes the development of hepatocellular carcinomas, a process that is accelerated by coexpression with transforming growth factor-alpha (TGF-alpha). TGF-alpha/c-Myc-derived hepatocellular carcinomas display reduced apoptotic levels compared with those of single c-Myc transgenic hepatocellular carcinomas, suggesting that TGF-alpha provides a survival advantage to c-Myc-transformed hepatocytes. Given that TGF-alpha/c-Myc hepatocellular carcinomas display constitutive NF-kappa B activity, here, we have tested the hypothesis that enforced expression of TGF-alpha results in constitutive NF-kappa B activation and enhanced cell survival using TGF-alpha/c-Myc-derived hepatocellular carcinoma cell lines. We show that TGF-alpha induces NF-kappa B through the phosphatidylinositol 3-kinase/Akt axis in these bitransgenic hepatocellular carcinomas. Furthermore, we found that adenovirus-mediated inhibition of NF-kappa B activity impairs the ability of TGF-alpha/c-Myc-derived tumor cells to grow in an anchorage-independent fashion due to sensitization to c-Myc-induced apoptosis. Lastly, we show that NF-kappa B inhibits c-Myc-induced activation of caspase-9 and caspase-3 through up-regulation of the antiapoptotic target genes Bcl-X-L and X-linked inhibitor of apoptosis (XIAP). Overall, these results underscore a crucial role of NF-kappa B in disabling apoptotic pathways initiated by oncogenic transformation.