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-κB (NF-κB) 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-α (TGF-α). TGF-α/c-Myc–derived hepatocellular carcinomas display reduced apoptotic levels compared with those of single c-Myc transgenic hepatocellular carcinomas, suggesting that TGF-α provides a survival advantage to c-Myc-transformed hepatocytes. Given that TGF-α/c-Myc hepatocellular carcinomas display constitutive NF-κB activity, here, we have tested the hypothesis that enforced expression of TGF-α results in constitutive NF-κB activation and enhanced cell survival using TGF-α/c-Myc–derived hepatocellular carcinoma cell lines. We show that TGF-α induces NF-κB through the phosphatidylinositol 3-kinase/Akt axis in these bitransgenic hepatocellular carcinomas. Furthermore, we found that adenovirus-mediated inhibition of NF-κB activity impairs the ability of TGF-α/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-κB 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-κB in disabling apoptotic pathways initiated by oncogenic transformation.