TY - JOUR
T1 - Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells
AU - Saha, Debabrata
AU - Datta, Pran K.
AU - Sheng, Hongmiao
AU - Morrow, Jason D.
AU - Wada, Michihiko
AU - Moses, Harold L.
AU - Beauchamp, R. Daniel
N1 - Funding Information:
Abbreviations: COX-2, cyclooxygenase-2; PG, prostaglandins; EGF, epidermal growth factor; bFGF, basic fibroblast growth factor; TGF-β, transforming growth factor-β; MAPK/ ERK, mitogen-activated protein kinase; MEK MAPK kinase; CDK4, cyclin dependent kinase 4; JNK, c-jun N-terminal kinase; NaBu, Sodium butyrate. Address all correspondence to: R. Daniel Beauchamp, MD, Department of Surgery, Vanderbilt University Medical Center D5230 MCN, 21st Avenue South, Nashville, TN 37232-2730. 1This work was s upported by NIH grant CA69457, CA77839 and DK52334 (to R.D.B.); NIH grant DK48831, GM42056, GM15431, DK26637 and CA77839 (to J.D.M.); and NIH grant CA 42572 (to H.L.M.) and the Vanderbilt Cancer Center support grant CA68485. J.D.M. is the recipient of a Burroughs-Wellcome fund clinical scientist award in translational research. Received 25 June 1999; Accepted 17 August 1999.
PY - 1999/12
Y1 - 1999/12
N2 - 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.
AB - 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.
KW - Apoptosis
KW - COX-2
KW - EGF
KW - TGF-β
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U2 - 10.1038/sj.neo.7900051
DO - 10.1038/sj.neo.7900051
M3 - Article
C2 - 10935498
AN - SCOPUS:0033290356
SN - 1522-8002
VL - 1
SP - 508
EP - 517
JO - Neoplasia
JF - Neoplasia
IS - 6
ER -