Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression

  • Br J Cancer. 2018 Jan;118(2):213-223. doi: 10.1038/bjc.2017.393.
Eiji Kashiwagi  1  2 ,  Satoshi Inoue  1  2  3  4 ,  Taichi Mizushima  1  2  3  4 ,  Jinbo Chen  3  4 ,  Hiroki Ide  1  2 ,  Takashi Kawahara  1  2  3 ,  Leonardo O Reis  1  2 ,  Alexander S Baras  1  2 ,  George J Netto  1  2 ,  Hiroshi Miyamoto  1  2  3  4  5
Affiliations
  • 1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 2. James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • 3. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 4. James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 5. Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
PMID: 29123257 DOI: 10.1038/bjc.2017.393
Abstract

Background: We investigated the role of prostaglandin receptors (e.g. prostaglandin E2 receptor 2 (EP2), EP4) and the efficacy of celecoxib in urothelial tumourigenesis and Cancer progression.

Methods: We performed immunohistochemistry in bladder Cancer (BC) tissue microarrays, in vitro transformation assay in a normal urothelial SVHUC line, and western blot/reverse transcription-polymerase chain reaction/cell growth assays in BC lines.

Results: EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those who were resistant to cisplatin-based neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumours or positivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality, respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene considerably increased and decreased the expression of EP2/EP4 and Phosphatase and tensin homologue (PTEN), respectively. Treatment with selective EP2/EP4 antagonist or celecoxib also resulted in prevention in 3-methylcholanthrene-induced neoplastic transformation of SVHUC cells. In BC lines, EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression. Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated and reduced, respectively, in cisplatin-resistant BC sublines.

Conclusions: EP2/EP4 activation correlates with induction of urothelial Cancer initiation and outgrowth, as well as chemoresistance, presumably via downregulating PTEN expression.

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