S-Space Graduate School of Convergence Science and Technology (융합과학기술대학원) Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과) Journal Papers (저널논문_분자의학 및 바이오제약학과)
15-Deoxy-Delta(12,14)-prostaglandin J(2) induces expression of 15-hydroxyprostaglandin dehydrogenase through Elk-1 activation in human breast cancer MDA-MB-231 cells
- Kim, Hye-Rim; Lee, Ha-Na; Lim, Kyu; Surh, Young-Joon; Na, Hye-Kyung
- Issue Date
- Mutation Research, Vol.768, pp.6-15
- 15-Hydroxyprostaglandin dehydrogenase; Breast cancer; 15-Deoxy-Delta(12,14)-prostaglandin J(2); Elk-1; ROS
- Overproduction of prostaglandin E-2 (PGE(2)) has been reported to be implicated in carcinogenesis. The intracellular level of PGE(2) is maintained not only by its biosynthesis, but also by inactivation/degradation. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of oncogenic PGE(2) to a biologically inactive keto metabolite. In the present study, we demonstrate that 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), one of the terminal products of cyclooxygenase-2, updregulates the expression and the activity of 15-PGDH in human breast cancer MDA-MB-231 cells. By using deletion constructs of the 15-PGDH promoter, we have found that E-twenty six (Ets) is the most essential determinant for 15-PGDH induction. 15d-PGJ(2) induced phosphorylation of Elk-1, one of Ets transcription factor family members, in the nucleus. Knockdown of Elk-1 abolished the ability of 15d-PGJ(2) to upregulate 15-PGDH expression. Furthermore, 15d-PGJ(2)-mediated activation of Elk-1 was found to be dependent on activation of extracellular-signal related kinase (ERK) 1/2. Treatment of U0126, a pharmacological inhibitor of MEK1/2-ERK, abolished phosphorylation and DNA binding of Elk-1 as well as 15-PGDH induction in 15d-PGJ(2)-treated MDA-MB-231 cells. Moreover, 15d-PGJ(2) generated reactive oxygen species (ROS), which contribute to the expression of 15-PGDH as well as phosphorylation of ERK1/2 and Elk-1. 15d-PGJ(2) inhibited the migration of MDA-MB-231 cells, which was attenuated by transient transfection with 15-PGDH siRNA. Taken together, these findings suggest that 15d-PGJ(2) induces the expression of 15-PGDH through ROS-mediated activation of ERK1/2 and subsequently Elk-1 in the MDA-MB-231 cells, which may contribute to tumor suppressive activity of this cyclopentenone prostaglandin. (C) 2014 Elsevier B.V. All rights reserved.
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