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Prostaglandin E₂ Mediates Phosphorylation and Down-Regulation of the Tuberous Sclerosis-2 Tumor Suppressor (Tuberin) in Human Endometrial Adenocarcinoma Cells via the Akt Signaling Pathway

MRC Human Reproductive Sciences Unit (K.J.S., S.B., R.A.A., H.N.J.), Centre for Reproductive Biology, and Department of Pathology (A.R.W.W.), The University of Edinburgh Academic Center, Edinburgh EH16 4SB, United Kingdom

Address all correspondence and requests for reprints to: Dr. Henry N. Jabbour, MRC Human Reproductive Sciences Unit, Center for Reproductive Biology, The University of Edinburgh Academic Center, 49 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SB, United Kingdom. E-mail: h.jabbour{at}hrsu.mrc.ac.uk.

Prostaglandin (PG) E₂ promotes tumor growth via interaction with its G protein-coupled receptors and activation of intracellular signaling. Tuberous sclerosis 2 (tuberin) is a tumor suppressor, which negatively regulates cell growth. Its phosphorylation results in its inactivation and targeted down- regulation, thus lifting the growth inhibition effects. This study investigated the expression and localization of tuberin in neoplastic and normal endometrium and the effect of PGE₂ on phosphorylation of tuberin via the Akt pathway. Quantitative RT-PCR and Western blot analysis demonstrated reduced expression of tuberin in neoplastic tissue, compared with normal endometrial tissue. Tuberin expression was localized by immunohistochemistry to the glandular epithelial compartment in neoplastic and normal endometrium. We investigated the effect of PGE₂ on phosphorylation of tuberin via the Akt pathway. Treatment of neoplastic and normal endometrium with 100 nM PGE₂ enhanced phosphorylated tuberin immunoreactivity in the glandular epithelium. PGE₂ also phosphorylated Akt and tuberin in Ishikawa endometrial adenocarcinoma cells, leading to a reduction in expression of total tuberin protein. Cotreatment of cells with wortmannin or LY294002 inhibited the PGE₂-induced phosphorylation of Akt and tuberin. These data suggest that PGE₂ signaling may promote endometrial tumorigenesis by inactivation of tuberin after its phosphorylation via the Akt signaling pathway.