title: Deficient DNA damage signaling leads to chemoresistance to cisplatin in oral cancer.
abstract: Activation of the cellular DNA damage response (DDR) is an important determinant of cell sensitivity to cisplatin and other chemotherapeutic drugs that eliminate tumor cells through induction of DNA damage. It is therefore important to investigate whether alterations of the DNA damage-signaling pathway confer chemoresistance in cancer cells and whether pharmacologic manipulation of the DDR pathway can resensitize these cells to cancer therapy. In a panel of oral/laryngeal squamous cell carcinoma (SCC) cell lines, we observed deficiencies in DNA damage signaling in correlation with cisplatin resistance, but not with DNA repair. These deficiencies are consistent with reduced expression of components of the ataxia telangiectasia mutated (ATM)-dependent signaling pathway and, in particular, strong upregulation of Wip1, a negative regulator of the ATM pathway. Wip1 knockdown or inhibition enhanced DNA damage signaling and resensitized oral SCC cells to cisplatin. In contrast to the previously reported involvement of Wip1 in cancer, Wip1 upregulation and function in these SCC cells is independent of p53. Finally, using xenograft tumor models, we showed that Wip1 upregulation promotes tumorigenesis and its inhibition improves the tumor response to cisplatin. Thus, this study reveals that chemoresistance in oral SCCs is partially attributed to deficiencies in DNA damage signaling, and Wip1 is an effective drug target for enhanced cancer therapy.
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Mosel
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Oakley
authors.forename: Aimin
authors.initials: A
authors.lastname: Peng
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C; D002945:Cisplatin