To determine signaling pathways responsible for modulation of COX-2 expression in nontransformed and transformed epithelial cells, we studied a rat intestinal epithelial (RIE) cell line expressing constitutively active Ras and RhoA. Expression of COX-2 protein was higher in RIE-RhoA(63L) (four-fold) and RIE-Ras(12V) (seven-fold) cells than in parental cells. Prior work suggests that Ras hyperactivity induces the expression of transforming growth factor (TGF) β and increases epidermal growth factor (EGF)-related peptide signaling—possible mechanisms for increased COX-2 expression. Expression of COX-2 was stimulated by TGFβ and TGFα in RIE and RIE-Rho(63L) cells, but not further stimulated in RIE-Ras(12V) cells. PD153035, an inhibitor of EGF receptor tyrosine kinase, and PD98059, an inhibitor of Erk, attenuated COX-2 expression in RIE and RIE-RhoA(63L). However, the high levels of COX-2 expression in RIE-Ras(12V) cells were not inhibited by either compound. Titration with a panneutralizing anti-TGFβ antibody did not decrease COX-2 in RIE-Ras(12V) cells, even with concurrent EGFR inhibition. Thus, stimulation of the EGF receptor is important in the modulation of COX-2 expression in nontransformed RIE and RIE-RhoA(63L) cells. In Ras-transformed cells, signaling by additional Ras effector pathways, perhaps the RhoA pathway, must be invoked. Identification of these pathways is critical for therapeutic manipulation of COX-2 expression
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