Overproduction of
prostaglandin E2 (
PGE2) has been reported to be implicated in
carcinogenesis. The intracellular level of
PGE2 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
PGE2 to a biologically inactive keto metabolite. In the present study, we demonstrate that 15-deoxy-Δ(12,14)-prostaglandin J2 (15 d-PGJ2), 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. 15 d-PGJ2 induced phosphorylation of Elk-1, one of
Ets transcription factor family members, in the nucleus. Knockdown of Elk-1 abolished the ability of 15 d-PGJ2 to upregulate
15-PGDH expression. Furthermore, 15 d-PGJ2-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 15 d-PGJ2-treated MDA-MB-231 cells. Moreover, 15 d-PGJ2 generated
reactive oxygen species (ROS), which contribute to the expression of
15-PGDH as well as phosphorylation of ERK1/2 and Elk-1. 15 d-PGJ2 inhibited the migration of MDA-MB-231 cells, which was attenuated by transient transfection with
15-PGDH siRNA. Taken together, these findings suggest that 15 d-PGJ2 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.