Roles of Akt/PKB and IKK complex in constitutive induction of NF-kappa B in hepatocellular carcinomas of transforming growth factor alpha/c-myc transgenic mice

NF-kappaB regulates liver cell death during development, regeneration, and neoplastic transformation. For example, we showed that oncogenic Ras- or Ra f-mediated transformation of rat liver epithelial cells (RLEs) led to alter ed NF-kappaB regulation through IKK complex activation, which rendered thes e cells more resistant to TGF-beta1-induced apoptosis. Thus, based on these findings, we sought to determine whether NF-kappaB could also be involved in tumor growth of liver cells in vivo. Hepatocellular carcinomas (HCCs) de rived from bitransgenic mice harboring TGF-alpha and c-myc transgenes targe ted specifically to the liver were compared with HCCs from c-myc single tra nsgenic mice. Tumors from bitransgenic mice are characterized by a higher f requency of appearance, lower apoptotic index, and a higher rate of cell pr oliferation. Here we show that NF-kappaB is activated in HCCs of double TGF -alpha /c-myc transgenic mice, but not of c-myc single transgenic mice, sug gesting that TGF-alpha mediates induction of NF-kappaB. Activation of the I KK complex was observed in the HCCs of double TGF-alpha /c-myc transgenic m ice, implicating this pathway in NF-kappaB induction. Lastly, activation of the Akt/ protein kinase B (PKB), which has recently been implicated in NF- kappaB activation by PDGF, TNF-alpha, and Ras, was also observed. Important ly, human HCC cell lines similarly displayed NF-kappaB activation. Thus, th ese studies elucidate an anti-apoptotic mechanism by a TGF-alpha -Akt/PKB-I KK pathway, which likely contributes to survival and proliferation, thereby accelerating c-myc-induced liver neoplastic development in vivo.