1. Transforming growth factor-alpha inhibits the intrinsic pathway of c-Myc-induced apoptosis through activation of nuclear factor-kappaB in murine hepatocellular carcinomas.
- Author
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Cavin LG, Wang F, Factor VM, Kaur S, Venkatraman M, Thorgeirsson SS, and Arsura M
- Subjects
- Animals, Apoptosis genetics, Blotting, Northern, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Caspase 3, Caspase 9, Caspases genetics, Caspases metabolism, Cell Line, Tumor, Electrophoretic Mobility Shift Assay, Liver Neoplasms genetics, Liver Neoplasms pathology, Mice, Mice, Transgenic, Protein Serine-Threonine Kinases, Transcription Factor RelA, Up-Regulation, Carcinoma, Hepatocellular metabolism, Liver Neoplasms metabolism, NF-kappa B metabolism, Proto-Oncogene Proteins c-myc physiology, Transforming Growth Factor alpha physiology
- Abstract
Nuclear factor-kappaB (NF-kappaB) 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-kappaB activity, here, we have tested the hypothesis that enforced expression of TGF-alpha results in constitutive NF-kappaB activation and enhanced cell survival using TGF-alpha/c-Myc-derived hepatocellular carcinoma cell lines. We show that TGF-alpha induces NF-kappaB through the phosphatidylinositol 3-kinase/Akt axis in these bitransgenic hepatocellular carcinomas. Furthermore, we found that adenovirus-mediated inhibition of NF-kappaB 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-kappaB 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-kappaB in disabling apoptotic pathways initiated by oncogenic transformation.
- Published
- 2005
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