Loss of p53 in stromal fibroblasts enhances tumor cell proliferation through nitric-oxide-mediated cyclooxygenase 2 activation

S. Wada, Y. Matsushita, Hiroshi Tazawa, W. Aoi, Y. Naito, A. Higashi, H. Ohshima, T. Yoshikawa

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Overexpression of cyclooxygenase 2 (COX-2) by stromal fibroblasts plays a critical role in the early stage of carcinogenesis. COX-2 expression is thought to be positively or negatively regulated by inflammatory chemical mediators or tumor suppressors. In this study, the contributions of inducible nitric oxide synthase (iNOS) and p53 to COX-2 expression were examined using mouse embryonic fibroblasts (MEFs) from wild-type, p53-deficient, iNOS-deficient, and p53/iNOS-deficient mice. These MEFs were treated with 1 μg/mL of lipopolysaccharide and 100 IU/mL of interferon gamma for up to 72 h. iNOS and COX-2 expression were analyzed by Western blotting. iNOS was induced earlier (16 h) in p53-deficient MEFs than in wild-type MEFs (48 h). Elevated expression of COX-2 was sustained for a longer duration in the p53-deficient MEFs. In contrast, COX-2 expression was reduced earlier in the iNOS-deficient MEFs. Addition of an exogenous NO donor (0.8 mM of S-nitroso-l-glutathione) to the iNOS-deficient MEFs augmented COX-2 expression. Co-culture with stimulated p53-deficient MEFs promoted cell proliferation of mouse rectal polyploid carcinoma CMT93 cells, but treatment with a COX-2-specific inhibitor counteracted this effect. These results suggest that loss of function of the p53 gene in stromal fibroblasts enhances COX-2 expression by enhancing iNOS expression and the resultant production of NO, contributing to the promotion of tumor growth.

Original languageEnglish
Pages (from-to)269-278
Number of pages10
JournalFree Radical Research
Volume49
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

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Cell proliferation
Cyclooxygenase 2
Fibroblasts
Tumors
Nitric Oxide Synthase Type II
Nitric Oxide
Chemical activation
Cell Proliferation
Neoplasms
Polyploidy
Cyclooxygenase 2 Inhibitors
p53 Genes
Coculture Techniques
Cell culture
Interferon-gamma
Glutathione
Lipopolysaccharides
Carcinogenesis
Genes
Western Blotting

Keywords

  • Carcinogenesis
  • Colorectal caner
  • Deficiency
  • Prostaglandin E
  • Stromal cells

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)

Cite this

Loss of p53 in stromal fibroblasts enhances tumor cell proliferation through nitric-oxide-mediated cyclooxygenase 2 activation. / Wada, S.; Matsushita, Y.; Tazawa, Hiroshi; Aoi, W.; Naito, Y.; Higashi, A.; Ohshima, H.; Yoshikawa, T.

In: Free Radical Research, Vol. 49, No. 3, 01.03.2015, p. 269-278.

Research output: Contribution to journalArticle

Wada, S. ; Matsushita, Y. ; Tazawa, Hiroshi ; Aoi, W. ; Naito, Y. ; Higashi, A. ; Ohshima, H. ; Yoshikawa, T. / Loss of p53 in stromal fibroblasts enhances tumor cell proliferation through nitric-oxide-mediated cyclooxygenase 2 activation. In: Free Radical Research. 2015 ; Vol. 49, No. 3. pp. 269-278.
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