title: Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies.
abstract: BACKGROUND
  Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors.
  
  
  METHODS
  Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration.
  
  
  RESULTS
  Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells.
  
  
  CONCLUSIONS
  In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC.
authors: Division of Head and Neck Surgery, Department of Surgery, David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, CHS 62-132, Los Angeles, CA 90095, USA. MStJohn@mednet.ucla.edu
authors: M A
authors: MA
authors: St John
authors: G
authors: G
authors: Wang
authors: J
authors: J
authors: Luo
authors: M
authors: M
authors: Dohadwala
authors: D
authors: D
authors: Hu
authors: Y
authors: Y
authors: Lin
authors: M
authors: M
authors: Dennis
authors: J M
authors: JM
authors: Lee
authors: D
authors: D
authors: Elashoff
authors: T
authors: T
authors: Lawhon
authors: S L
authors: SL
authors: Zaknoen
authors: F J
authors: FJ
authors: Burrows
authors: S M
authors: SM
authors: Dubinett
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000209:etiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases; D027361:Organic Anion Transporters / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D012907:Smoking / Q000009:adverse effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism
chemical_list: D015820:Cadherins; D052246:Cyclooxygenase 2 Inhibitors; D027361:Organic Anion Transporters; D011758:Pyrroles; C503526:SLCO2A1 protein, human; D013449:Sulfonamides; D014746:Vimentin; C514354:apricoxib; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase