Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells

Debabrata Saha, Pran K. Datta, Hongmiao Sheng, Jason D. Morrow, Michihiko Wada, Harold L. Moses, R. Daniel Beauchamp

Research output: Contribution to journalArticle

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Abstract

Increased expression of cyclooxygenase-2 (COX-2) expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, and the stimulation of angiogenesis. In the present studies, we found that transforming growth factor β1 (TGF-β1) and epidermal growth factor (EGF) synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2) production in mink lung epithelial (Mv1Lu) cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-β1-induced apoptosis in Mv1Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptotic effect of EGF receptor ligands. The combination of TGF-β1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1) cells and completely prevented sodium butyrate (NaBu)-induced apoptosis. The synergistic induction of COX-2 by TGF-β1 and EGF was not observed in R1B-L17 cells, a line derived from Mv1Lu cells that lacks the TGF-β type-1 receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-β1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, and SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-β1. These results suggest an important collaborative interaction of TGF-β1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.

Original languageEnglish (US)
Pages (from-to)508-517
Number of pages10
JournalNeoplasia
Volume1
Issue number6
StatePublished - Dec 1999

Fingerprint

Transforming Growth Factors
Cyclooxygenase 2
Epidermal Growth Factor
Epithelial Cells
Apoptosis
Epidermal Growth Factor Receptor
Prostaglandins
Mink
Butyric Acid
MAP Kinase Signaling System
Cyclooxygenase 2 Inhibitors
p38 Mitogen-Activated Protein Kinases
Insulin-Like Growth Factor I
Dinoprostone
Protein-Tyrosine Kinases
Extracellular Matrix
Lung Neoplasms
Carcinogenesis
Cell Culture Techniques
Ligands

Keywords

  • Apoptosis
  • COX-2
  • EGF
  • TGF-β

ASJC Scopus subject areas

  • Cancer Research

Cite this

Saha, D., Datta, P. K., Sheng, H., Morrow, J. D., Wada, M., Moses, H. L., & Beauchamp, R. D. (1999). Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells. Neoplasia, 1(6), 508-517.

Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells. / Saha, Debabrata; Datta, Pran K.; Sheng, Hongmiao; Morrow, Jason D.; Wada, Michihiko; Moses, Harold L.; Beauchamp, R. Daniel.

In: Neoplasia, Vol. 1, No. 6, 12.1999, p. 508-517.

Research output: Contribution to journalArticle

Saha, D, Datta, PK, Sheng, H, Morrow, JD, Wada, M, Moses, HL & Beauchamp, RD 1999, 'Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells', Neoplasia, vol. 1, no. 6, pp. 508-517.
Saha, Debabrata ; Datta, Pran K. ; Sheng, Hongmiao ; Morrow, Jason D. ; Wada, Michihiko ; Moses, Harold L. ; Beauchamp, R. Daniel. / Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells. In: Neoplasia. 1999 ; Vol. 1, No. 6. pp. 508-517.
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