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HER-2/neu raises SHP-2, stops IFN-gamma anti-proliferation in bladder cancer

Wen-Pin Su1, I-Hwi Tu, Shiao-Wen Hu

  • 1Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Biochemical and Biophysical Research Communications
|March 10, 2007
PubMed

Insights

Interferon-gamma (IFN-gamma) failed to inhibit HER-2/neu-overexpressing bladder cancer cells due to increased SHP-2 phosphatase. Inhibiting HER-2/neu reactivated IFN-gamma signaling, suggesting SHP-2 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • HER-2/neu overexpression is linked to poor prognosis in bladder cancer.
  • Interferon-gamma (IFN-gamma) is a cytokine with potential anti-cancer effects.
  • The Janus kinase (Jak)/Signal transducer and activator of transcription (Stat) pathway is crucial for IFN-gamma signaling.

Purpose of the Study:

  • To investigate the anti-proliferative effects of IFN-gamma in HER-2/neu-overexpressing human bladder cancer cells.
  • To elucidate the mechanism by which HER-2/neu overexpression suppresses IFN-gamma signaling.
  • To identify potential therapeutic targets for overcoming resistance to IFN-gamma in bladder cancer.

Main Methods:

  • Utilized human bladder cancer cell lines (TCC-N5, TCC-N10) transfected with HER-2/neu.
  • Assessed cell proliferation and Jak/Stat pathway activation following IFN-gamma stimulation.
  • Investigated the role of Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2) and its regulation by HER-2/neu.
  • Employed AG825, a specific HER-2/neu inhibitor, to evaluate its impact on SHP-2 expression and pathway reactivation.
  • Validated findings in a mouse bladder cancer cell line (MBT2) with constitutive HER-2/neu overexpression.

Main Results:

  • HER-2/neu-overexpressing bladder cancer cells showed resistance to IFN-gamma's anti-proliferative effects.
  • IFN-gamma stimulation did not activate the Jak/Stat pathway in these cells.
  • Upregulated SHP-2 phosphatase was identified in HER-2/neu-overexpressing cells.
  • Treatment with AG825 reduced SHP-2 expression and restored Jak2/Stat1 activation.
  • AG825 pretreatment re-sensitized cells to IFN-gamma's anti-proliferative activity.

Conclusions:

  • SHP-2 upregulation, regulated by HER-2/neu, suppresses IFN-gamma signaling in bladder cancer.
  • Targeting SHP-2 offers a potential strategy to overcome IFN-gamma resistance in HER-2/neu-driven bladder cancer.
  • HER-2/neu-mediated regulation of SHP-2 presents a novel therapeutic target in bladder cancer treatment.

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