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

C. W. Tsai, F. J. Lai, H. M. Sheu, Y. S. Lin, T. H. Chang, M. S. Jan, S. M. Chen, P. C. Hsu, T. T. Huang, T. C. Huang, M. C. Sheen, S. T. Chen, W. C. Chang, N. S. Chang, L. J. Hsu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressedWWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12-Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.

Original languageEnglish
Article numbere792
JournalCell Death and Disease
Volume4
Issue number9
DOIs
Publication statusPublished - Sep 2013

Fingerprint

Autophagy
Methotrexate
Squamous Cell Carcinoma
Apoptosis
Sirolimus
Down-Regulation
70-kDa Ribosomal Protein S6 Kinases
Proteins
Caspases
Tumor Cell Line
Drug Resistance
Small Interfering RNA
Oxidoreductases
Cell Death
Phosphorylation
Neoplasm Metastasis

Keywords

  • Apoptosis
  • Autophagy
  • Chemotherapy
  • Methotrexate
  • Tumor suppressor

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Tsai, C. W., Lai, F. J., Sheu, H. M., Lin, Y. S., Chang, T. H., Jan, M. S., ... Hsu, L. J. (2013). WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma. Cell Death and Disease, 4(9), [e792]. https://doi.org/10.1038/cddis.2013.308

WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma. / Tsai, C. W.; Lai, F. J.; Sheu, H. M.; Lin, Y. S.; Chang, T. H.; Jan, M. S.; Chen, S. M.; Hsu, P. C.; Huang, T. T.; Huang, T. C.; Sheen, M. C.; Chen, S. T.; Chang, W. C.; Chang, N. S.; Hsu, L. J.

In: Cell Death and Disease, Vol. 4, No. 9, e792, 09.2013.

Research output: Contribution to journalArticle

Tsai, CW, Lai, FJ, Sheu, HM, Lin, YS, Chang, TH, Jan, MS, Chen, SM, Hsu, PC, Huang, TT, Huang, TC, Sheen, MC, Chen, ST, Chang, WC, Chang, NS & Hsu, LJ 2013, 'WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma', Cell Death and Disease, vol. 4, no. 9, e792. https://doi.org/10.1038/cddis.2013.308
Tsai, C. W. ; Lai, F. J. ; Sheu, H. M. ; Lin, Y. S. ; Chang, T. H. ; Jan, M. S. ; Chen, S. M. ; Hsu, P. C. ; Huang, T. T. ; Huang, T. C. ; Sheen, M. C. ; Chen, S. T. ; Chang, W. C. ; Chang, N. S. ; Hsu, L. J. / WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma. In: Cell Death and Disease. 2013 ; Vol. 4, No. 9.
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abstract = "Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressedWWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12-Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.",
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AU - Lin, Y. S.

AU - Chang, T. H.

AU - Jan, M. S.

AU - Chen, S. M.

AU - Hsu, P. C.

AU - Huang, T. T.

AU - Huang, T. C.

AU - Sheen, M. C.

AU - Chen, S. T.

AU - Chang, W. C.

AU - Chang, N. S.

AU - Hsu, L. J.

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N2 - Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressedWWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12-Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.

AB - Squamous cell carcinoma (SCC) cells refractory to initial chemotherapy frequently develop disease relapse and distant metastasis. We show here that tumor suppressor WW domain-containing oxidoreductase (WWOX) (also named FOR or WOX1) regulates the susceptibility of SCC to methotrexate (MTX) in vitro and cure of SCC in MTX therapy. MTX increased WWOX expression, accompanied by caspase activation and apoptosis, in MTX-sensitive SCC cell lines and tumor biopsies. Suppression by a dominant-negative or small interfering RNA targeting WWOX blocked MTX-mediated cell death in sensitive SCC-15 cells that highly expressedWWOX. In stark contrast, SCC-9 cells expressed minimum amount of WWOX protein and resisted MTX-induced apoptosis. Transiently overexpressed WWOX sensitized SCC-9 cells to apoptosis by MTX. MTX significantly downregulated autophagy-related Beclin-1, Atg12-Atg5 and LC3-II protein expression and autophagosome formation in the sensitive SCC-15, whereas autophagy remained robust in the resistant SCC-9. Mechanistically, WWOX physically interacted with mammalian target of rapamycin (mTOR), which potentiated MTX-increased phosphorylation of mTOR and its downstream substrate p70 S6 kinase, along with dramatic downregulation of the aforementioned proteins in autophagy, in SCC-15. When WWOX was knocked down in SCC-15, MTX-induced mTOR signaling and autophagy inhibition were blocked. Thus, WWOX renders SCC cells susceptible to MTX-induced apoptosis by dampening autophagy, and the failure in inducing WWOX expression leads to chemotherapeutic drug resistance.

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