ArticleCell death & disease2013
WWOX suppresses autophagy for inducing apoptosis in methotrexate-treated human squamous cell carcinoma.
Article in Cell death & disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 48 citations in OpenAlex.
- WWOX Induction Promotes Bcl-XCells · 2026Article
- Review
- Novel Hydrogel-Mediated Lentiviral Gene Delivery via Intravesical Administration for Bladder Cancer Treatment.Pharmaceutics · 2025Article
- Loss of fragile WWOX gene leads to senescence escape and genome instability.Cellular and molecular life sciences : CMLS · 2023Article
- PrePCI: A structure- and chemical similarity-informed database of predicted protein compound interactions.Protein science : a publication of the Protein Society · 2023Article
- Autophagy and Skin Diseases.Frontiers in pharmacology · 2022Review
- Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299.Communications biology · 2021Article
- Autophagy-A Hidden but Important Actor on Oral Cancer Scene.International journal of molecular sciences · 2020Review
- MiR-214 Mediates Cell Proliferation and Apoptosis of Nasopharyngeal Carcinoma Through Targeting Both WWOX and PTEN.Cancer biotherapy & radiopharmaceuticals · 2020Article
- Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer's Disease.International journal of molecular sciences · 2020Review
- ARID1A prevents squamous cell carcinoma initiation and chemoresistance by antagonizing pRb/E2F1/c-Myc-mediated cancer stemness.Cell death and differentiation · 2020Article
- Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice.Acta neuropathologica communications · 2020Article
- Article
- The downregulation of WWOX induces epithelial-mesenchymal transition and enhances stemness and chemoresistance in breast cancer.Experimental biology and medicine (Maywood, N.J.) · 2018Article
- Sp110 enhances macrophage resistance toOncotarget · 2017Article
- WWOX sensitises ovarian cancer cells to paclitaxel via modulation of the ER stress response.Cell death & disease · 2017Article
- EGFR Family Members' Regulation of Autophagy Is at a Crossroads of Cell Survival and Death in Cancer.Cancers · 2017Review
- Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.Oncotarget · 2017Article
- Bubbling cell death: A hot air balloon released from the nucleus in the cold.Experimental biology and medicine (Maywood, N.J.) · 2016Review
- HYAL-2-WWOX-SMAD4 Signaling in Cell Death and Anticancer Response.Frontiers in cell and developmental biology · 2016Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 expressed WWOX. 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.