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Signaling and Regulation

Transforming Growth Factor- Inhibits the Intrinsic Pathway of c-Myc-Induced Apoptosis through Activation of Nuclear Factor-B in Murine Hepatocellular Carcinomas

¹ Department of Pharmacology, Center for Anticancer Drug Research, College of Medicine, University of Tennessee Cancer Institute, Memphis, Tennessee and ² Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Marcello Arsura, Department of Pharmacology, Center for Anticancer Drug Research, College of Medicine, University of Tennessee Cancer Institute, 874 Union Avenue, Memphis, TN 38163. Phone: 901-448-1733; Fax: 901-448-7206. E-mail: marsura{at}utmem.edu

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

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