Roles of Akt/PKB and IKK complex in constitutive induction of NF-kappaB 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 Raf-mediated transformation of rat liver epithelial cells (RLEs) led to altered NF-kappaB regulation through IKK complex activation, which rendered these 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) derived from bitransgenic mice harboring TGF-alpha and c-myc transgenes targeted specifically to the liver were compared with HCCs from c-myc single transgenic mice. Tumors from bitransgenic mice are characterized by a higher frequency of appearance, lower apoptotic index, and a higher rate of cell proliferation. 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, suggesting that TGF-alpha mediates induction of NF-kappaB. Activation of the IKK complex was observed in the HCCs of double TGF-alpha/c-myc transgenic mice, 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. Importantly, human HCC cell lines similarly displayed NF-kappaB activation. Thus, these studies elucidate an anti-apoptotic mechanism by a TGF-alpha-Akt/PKB-IKK pathway, which likely contributes to survival and proliferation, thereby accelerating c-myc-induced liver neoplastic development in vivo.
Factor
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Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, Bethesda, MD, USA.
Oliver
A L
AL
Panta
G R
GR
Thorgeirsson
S S
SS
Sonenshein
G E
GE
Arsura
M
M
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000502:physiology*; D002455:Cell Division; D004789:Enzyme Activation; D015870:Gene Expression; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000096:biosynthesis* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000502:physiology; D016601:RNA-Binding Proteins; D016211:Transforming Growth Factor alpha / Q000235:genetics* / Q000502:physiology
D002352:Carrier Proteins; C491967:Elp1 protein, rat; C491968:Ikbkap protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D016211:Transforming Growth Factor alpha; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt