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Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
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Nuclear EGFR impairs ASPP2-p53 complex-induced apoptosis by inducing SOS1 expression in hepatocellular carcinoma

Kai Liu1,2, Tao Jiang1, Yabo Ouyang1,2

  • 1Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.

Oncotarget
|May 19, 2015
PubMed

Insights

ASPP2 induces apoptosis in hepatoma cells by enhancing p53

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Pathways

Background:

  • Apoptosis evasion is a hallmark of cancer, contributing to treatment resistance in hepatoma.
  • ASPP2 (Apoptosis-Stimulating Protein of p53) interacts with p53 to promote apoptosis.
  • EGFR signaling can influence cell survival pathways.

Purpose of the Study:

  • To elucidate the mechanism by which ASPP2 regulates apoptosis in hepatoma cells.
  • To investigate the role of EGFR and downstream pathways in modulating ASPP2-induced apoptosis.
  • To identify potential therapeutic targets for overcoming apoptosis resistance in hepatoma.

Main Methods:

  • Transient and long-term overexpression of ASPP2 in hepatoma cells.
  • Analysis of p53 binding to pro-apoptotic gene promoters.
  • Investigating the EGFR/SOS1/HRAS/PI3K/AKT pathway activation.
  • In vivo assays to assess tumor growth and apoptosis resistance.
  • Blocking nuclear EGFR translocation.

Main Results:

  • Short-term ASPP2 overexpression enhanced p53-mediated apoptosis.
  • Long-term ASPP2 overexpression led to apoptosis resistance due to p53 release.
  • EGFR signaling via SOS1 activates AKT, promoting Bcl-2 interaction with p53.
  • Blocking EGFR nuclear translocation restored ASPP2's pro-apoptotic function.
  • EGFR/SOS1 pathway activation confers resistance to cisplatin-induced apoptosis.

Conclusions:

  • EGFR signaling promotes hepatoma cell survival by inhibiting ASPP2-p53 complex-induced apoptosis.
  • The EGFR/SOS1/AKT/Bcl-2 axis represents a common mechanism of apoptosis evasion in hepatoma.
  • Combined blockade of EGFR and SOS1 may represent a viable therapeutic strategy for hepatoma treatment.
Keywords:
ASPP2EGFRSOS1apoptosisp53

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