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Loss of PTEN causes SHP2 activation, making lung cancer cells unresponsive to IFN-γ

Chia-Ling Chen1, Tzu-Hui Chiang2, Po-Chun Tseng2

  • 1Translational Research Center, Taipei Medical University, Taipei 110, Taiwan.

Biochemical and Biophysical Research Communications
|September 20, 2015
PubMed

Insights

Decreased phosphatase and tensin homolog deleted on chromosome 10 (PTEN) impairs immune interferon-gamma (IFN-γ) signaling in lung cancer. This impairment involves reactive oxygen species (ROS) and SHP2 activation, hindering cancer immunoediting.

Area of Science:

  • Oncology
  • Immunology
  • Cellular Signaling

Background:

  • Src homology-2 domain-containing phosphatase (SHP) 2 is an oncogenic phosphatase that inhibits type II immune interferon-gamma (IFN-γ) signaling.
  • Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor protein crucial for cellular responses to IFN-γ.

Purpose of the Study:

  • To investigate how decreased PTEN impacts IFN-γ signaling in lung adenocarcinoma cells.
  • To elucidate the role of SHP2 and reactive oxygen species (ROS) in PTEN-mediated IFN-γ resistance.

Main Methods:

  • Comparison of human lung adenocarcinoma cell lines with varying PTEN expression (A549 vs. PC14PE6/AS2).
  • Artificial silencing of PTEN in A549 cells.
  • Assessment of IFN-γ-induced signaling (IRF1 activation, CD54 expression), cell proliferation inhibition, and cytotoxicity.
  • Evaluation of SHP2 activation by ROS.
  • Inhibition of ROS and SHP2 to rescue IFN-γ responsiveness.

Main Results:

  • Lung cancer cells with naturally low or silenced PTEN exhibit reduced responsiveness to IFN-γ.
  • IFN-γ-induced inhibition of cell proliferation and cytotoxicity are defective in PTEN-deficient cells.
  • PTEN deficiency leads to aberrant activation of SHP2 by ROS.
  • Inhibition of ROS and SHP2 restores sensitivity to IFN-γ in PTEN-deficient cells.

Conclusions:

  • A decrease in PTEN facilitates ROS/SHP2 signaling pathways.
  • This signaling cascade renders lung cancer cells unresponsive to IFN-γ.
  • Targeting ROS and SHP2 may restore IFN-γ sensitivity in PTEN-deficient lung cancers.
Keywords:
IFN-γPTENROSSHP2Signaling

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