INDUCTION OF CYCLOOXYGENASE-2 EXPRESSION BY PEROXISOME PROLIFERATORS AND NON-TETRADECANOYLPHORBOL 12,13-MYRISTATE-TYPE TUMOR PROMOTERS IN IMMORTALIZED MOUSE-LIVER CELLS

Increased expression of cyclooxygenase-2 (COX-2), the rate-limiting en zyme in prostaglandin synthesis, has been associated with growth regul ation and carcinogenesis in several systems, COX-2 is known to be indu ced by cytokines and the skin tumor promoter 12-tetradecanoylphorbol-1 3-myristate (TPA). In the present study, we investigated the effects o f several non-TPA-type tumor promoters on COX-2 expression in immortal ized mouse liver cells. Specifically, we tested peroxisome proliferato rs (PPs), which are rodent liver tumor promoters that cause gross alte rations in cellular lipid metabolism, the rodent liver tumor promoter phenobarbital, and the skin tumor promoters okadaic acid and thapsigar gin. The PPs Wy-14643, mono-ethylhexyl phthalate, clofibrate, ciprofib rate ethyl ester, and eicosatetraynoic acid each caused large increase s in COX-2 mRNA and protein, with maximal expression seen approximatel y 10 h after treatment of quiescent cells. COX-2 expression was also i nduced by thapsigargin, okadaic acid, and calcium ionophore A23187, bu t not by phenobarbital or the steroid PP dehydroepiandrosterone sulfat e. Induction of COX-2 expression generally resulted in increased syn t hesis of prostaglandin E(2) (PGE(2)). However, the PPs caused little o r no increase in PGE(2) levels, and they inhibited serum-induced PGE(2 ) synthesis. Unlike nonsteroidal anti-inflammatory drugs, the PPs do n ot directly inhibit cyclooxygenase enzyme activity in vitro, Thus, PPs regulate prostaglandin metabolism via both positive (COX-2 induction) and inhibitory mechanisms, In summary, the strong induction of COX-2 expression by PPs, thapsigargin, and okadaic acid suggests a possible role for COX-2 in the growth regulatory activity of these non-TPA-type tumor promoters.