Abnormal up-regulation of cyclooxygenase-2 (COX-2) expression has been considered as a key oncogenic event in inflammation-associated human colon carcinogenesis. It was reported that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a physiological antagonist of COX-2 in its catabolism, is ubiquitously lost in human colon cancer, and hence considered as a tumor suppressor. However, the molecular mechanisms underlying regulation of 15-PGDH expression in colon carcinogenesis remain largely unresolved. In the present study, we found that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products of COX-mediated arachidonic acid metabolism, upregulates the expression of 15-PGDH in the human colon cancer HCT116 cells in a time and concentration-dependent manners. 15d-PGJ2 treatment (10 μM) significantly upregulated the expression of 15-PGDH and its mRNA transcript. 15-PGDH activity was also elevated by 15d-PGJ2 treatment. In a subsequent experiment, we performed cDNA microarray analysis with HCT116 cells exposed to 15d-PGJ2 (10 µM) for 3 h. We observed that C/EBP delta, FOS-like antigen 1, and c-Jun (AP-1) were the most highly induced genes upon treatment with 15d-PGJ2. Based on these findings, we determined whether 15d-PGJ2 could activate the DNA binding of AP-1, a representative transcription factor that preferentially binds to the promoter region of 15-PGDH. 15d-PGJ2 caused increased DNA binding activity of AP-1 in HCT116 cells. Moreover, siRNA knock down of c-Jun, a major subunit of AP-1, significantly reduced 15-PGDH expression as well as AP-1 DNA binding induced by 15d-PGJ2. To elucidate the upstream signaling pathways responsible for AP-1 activation and 15-PGDH expression induced by 15d-PGJ2, we examined the effect of this cyclopentenone prostaglandin on the activation of mitogen-activated protein kinases (MAPKs), such as ERK, p38 and JNK, and also Akt. We observed that a pharmacological inhibition of Akt/PKB with LY294002 abrogated the 15d-PGJ2-induced 15-PGDH expression and AP-1 DNA binding activity, while inhibitors of MAPKs failed to affect these events. Taken together, these finding suggest that 15d-PGJ2 upregulates the expression of 15-PGDH via Akt-mediated AP-1 activation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1483.