Insulin-like growth factor-1 upregulates cyclooxygenase-2 expression in human ovarian cancer cells

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Recent studies have shown that elevated levels of insulin-like growth factor-1 (IGF-1) are associated with ovarian carcinogenesis and progression. However, the mechanisms by which IGF-1 contributes to ovarian cancer development remain largely unknown. Cyclooxygenase-2 (COX-2), the rate-limiting enzyme for prostaglandin production, has been emerging as a crucial mediator in the pathogenesis of human malignancies. Here we report that, IGF-1 greatly induced COX-2 mRNA and protein expression and consequent PGE2 production in human ovarian cancer cells. IGF-1 treatment markedly increased COX-2 promoter activity. IGF-1 also stabilized COX-2 mRNA and increased the activity of COX-2 3′-untranslated region (3′-UTR), which appeared independent on the conserved AU-rich elements. These results indicate that IGF-1 regulates COX-2 expression at both transcriptional and posttranscriptional levels. To investigate the signaling pathways involved in IGF-1-induced COX-2 expression, we found that inhibition of PI3K activity by wortmannin or LY294002 prevented IGF-1-induced COX-2 expression. Wortmannin inhibited IGF-1-induced stabilization of COX-2 mRNA, but not the activation of COX-2 transcription. By using specific pharmaceutical inhibitors, we demonstrated that ERK1/2, p38 and JNK were also required for IGF-1-mediated COX-2 expression. However, while ERK1/2 and p38 MAPK were important for both COX-2 gene transcription and mRNA stability, JNK affected only COX-2 mRNA stability. IGF-1 increased PKC activity in the cells. Inhibition of PKC activation by bisindolylmaleimide blocked IGF-1-induced COX-2 expression at transcriptional level and mRNA stability. Taken together, these data indicate that IGF-1 induces COX-2 expression through transcriptional and posttranscriptional mechanisms via multiple signaling pathways in human ovarian cancer cells. Our data suggest that IGF-1 may regulate ovarian cancer development through COX-2 expression.