15-Deoxy-Δ^12,14-prostaglandin J₂ induces expression of 15-hydroxyprostaglandin dehydrogenase through Elk-1 activation in human breast cancer MDA-MB-231 cells

다국어 초록 (Multilingual Abstract)

Overproduction of prostaglandin E<SUB>2</SUB> (PGE<SUB>2</SUB>) has been reported to be implicated in carcinogenesis. The intracellular level of PGE<SUB>2</SUB> 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<SUB>2</SUB> to a biologically inactive keto metabolite. In the present study, we demonstrate that 15-deoxy-Δ<SUP>12,14</SUP>-prostaglandin J<SUB>2</SUB> (15d-PGJ<SUB>2</SUB>), 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<SUB>2</SUB> 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<SUB>2</SUB> to upregulate 15-PGDH expression. Furthermore, 15d-PGJ<SUB>2</SUB>-mediated activation of Elk-1 was found to be dependent on activation of extracellular-signal related kinase (ERK) ½. Treatment of U0126, a pharmacological inhibitor of MEK½-ERK, abolished phosphorylation and DNA binding of Elk-1 as well as 15-PGDH induction in 15d-PGJ<SUB>2</SUB>-treated MDA-MB-231 cells. Moreover, 15d-PGJ<SUB>2</SUB> generated reactive oxygen species (ROS), which contribute to the expression of 15-PGDH as well as phosphorylation of ERK½ and Elk-1. 15d-PGJ<SUB>2</SUB> 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<SUB>2</SUB> induces the expression of 15-PGDH through ROS-mediated activation of ERK½ and subsequently Elk-1 in the MDA-MB-231 cells, which may contribute to tumor suppressive activity of this cyclopentenone prostaglandin.