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Therapeutic Strategies for Hepatocellular Carcinoma Based on Analyses for Resistance to Apoptosis Mediated by Activation of Intracellular Signal Pathways

  • Toshifumi Ito
  • Yutaka Sasaki
  • Harumasa Yoshihara
  • Kunio Suzuki
  • Eiji Masuda
  • Yukinori Yamada
  • Keiichi Arai
  • Takenobu Kamada
  • Norio Hayashi
  • Jack R. Wands
Conference paper

Abstract

Evidence clearly demonstrates that transforming hepatocytes are gaining phenotypes, either accelerating cell cycles or resisting apoptosis, during hepatocarcinogenesis. Disorder of intracellular signaling seems to be closely related to the acquisition of such malignant phenotypes. Thus it is important to understand how the intracellular signaling is constitutively activated or improperly regulated. It is beneficial to clarify these pathways for the sake of preparing new therapeutic strategies against human hepatocellular carcinoma (HCC). On the other hand, insulin is a hepatotrophic factor that stimulates growth of normal hepatocytes and HCC-derived cell lines. The insulin receptor substrate-1 protein (IRS-1) is a specific substrate for insulin receptor tyrosine kinase. Expression and tyrosyl phosphorylation of IRS-1 plays an important role during normal hepatocyte growth, and the gene is overexpressed in HCC tissue. Previously, we reported that IRS-1 could induce cellular transformation similar to a dominant oncogene. Interestingly, it has been reported that several cytokines, such as insulin and insulin-like growth factors, could inhibit apoptotic phenomena. Here we reviewed the role of IRS-1 overexpression in hepatic carcinogenesis from the viewpoint of transforming activities and acquisition of resistance to apoptosis. These analyses may permit a new understanding of oncogenes, by which overexpression cells could acquire not only the transforming phenotype but also the ability to escape from programmed cell death, thereby becoming resistant to therapy. Moreover, they may lead to new therapeutic strategies for HCC, targeting the intracellular signaling molecules.

Keywords

Insulin Receptor MAPK Cascade Insulin Receptor Tyrosine Kinase Insulin Receptor Tyrosine Kinase Activity Tyrosyl Phosphorylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Japan 2001

Authors and Affiliations

  • Toshifumi Ito
    • 1
  • Yutaka Sasaki
    • 2
  • Harumasa Yoshihara
    • 1
  • Kunio Suzuki
    • 1
  • Eiji Masuda
    • 1
  • Yukinori Yamada
    • 1
  • Keiichi Arai
    • 1
  • Takenobu Kamada
    • 1
  • Norio Hayashi
    • 2
  • Jack R. Wands
    • 3
  1. 1.Department of GastroenterologyOsaka Rosai HospitalSakai, OsakaJapan
  2. 2.Department of Molecular TherapeuticsOsaka University Postgraduate School of MedicineSuita, OsakaJapan
  3. 3.The Liver Research CenterRhode Island Hospital and Brown University School of MedicineProvidenceUSA

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