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Roles of Akt/PKB and IKK complex in constitutive induction of NF‐κB in hepatocellular carcinomas of transforming growth factor α/c‐ myc transgenic mice
Author(s) -
Factor Valentina,
Oliver Aundrea L.,
Panta Ganesh R.,
Thorgeirsson Snorri S.,
Sonenshein Gail E.,
Arsura Marcello
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.25270
Subject(s) - hccs , protein kinase b , cancer research , tgf alpha , biology , genetically modified mouse , transgene , transforming growth factor , cell growth , nf κb , iκb kinase , signal transduction , microbiology and biotechnology , growth factor , receptor , hepatocellular carcinoma , biochemistry , gene
NF‐κB 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‐κB regulation through IKK complex activation, which rendered these cells more resistant to TGF‐β1‐induced apoptosis. Thus, based on these findings, we sought to determine whether NF‐κB could also be involved in tumor growth of liver cells in vivo . Hepatocellular carcinomas (HCCs) derived from bitransgenic mice harboring TGF‐α 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‐κB is activated in HCCs of double TGF‐α/c‐ myc transgenic mice, but not of c‐ myc single transgenic mice, suggesting that TGF‐α mediates induction of NF‐κB. Activation of the IKK complex was observed in the HCCs of double TGF‐α/c‐ myc transgenic mice, implicating this pathway in NF‐κB induction. Lastly, activation of the Akt/protein kinase B (PKB), which has recently been implicated in NF‐κB activation by PDGF, TNF‐α, and Ras, was also observed. Importantly, human HCC cell lines similarly displayed NF‐κB activation. Thus, these studies elucidate an anti‐apoptotic mechanism by a TGF‐α‐Akt/PKB‐IKK pathway, which likely contributes to survival and proliferation, thereby accelerating c‐ myc ‐induced liver neoplastic development in vivo .