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WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma

C-W Tsai1, F J Lai, H M Sheu

  • 1Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.

Cell Death & Disease
|September 7, 2013
PubMed

Insights

The tumor suppressor WW domain-containing oxidoreductase (WWOX) increases susceptibility of squamous cell carcinoma (SCC) to methotrexate (MTX) therapy. Low WWOX expression causes resistance by preventing MTX-induced apoptosis and autophagy inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Squamous cell carcinoma (SCC) often relapses after chemotherapy.
  • Drug resistance in SCC limits treatment efficacy.
  • Understanding molecular mechanisms of chemoresistance is crucial.

Purpose of the Study:

  • To investigate the role of WW domain-containing oxidoreductase (WWOX) in methotrexate (MTX) sensitivity in SCC.
  • To elucidate the mechanism by which WWOX influences MTX-induced apoptosis and autophagy.

Main Methods:

  • Assessed WWOX expression in MTX-sensitive and resistant SCC cell lines and patient biopsies.
  • Utilized dominant-negative and small interfering RNA (siRNA) to modulate WWOX levels.
  • Examined caspase activation, apoptosis, and autophagy markers (Beclin-1, Atg12-Atg5, LC3-II).
  • Investigated the interaction between WWOX and mammalian target of rapamycin (mTOR) signaling pathway.

Main Results:

  • MTX treatment increased WWOX expression, caspase activation, and apoptosis in sensitive SCC cells.
  • WWOX suppression or low endogenous WWOX conferred resistance to MTX-induced cell death.
  • Overexpression of WWOX sensitized resistant SCC cells to MTX.
  • MTX downregulated autophagy markers and autophagosome formation in sensitive SCC cells, while autophagy remained active in resistant cells.
  • WWOX physically interacted with mTOR, enhancing MTX-induced mTOR phosphorylation and subsequent autophagy inhibition.

Conclusions:

  • WWOX sensitizes SCC cells to MTX-induced apoptosis by suppressing autophagy.
  • Failure to induce WWOX expression is a key mechanism of MTX resistance in SCC.
  • Targeting WWOX may represent a therapeutic strategy to overcome chemoresistance in SCC.

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