This Article Full Text Full Text (PDF) Supplemental Data Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hoekstra, A. V. Articles by Kim, J. J. Search for Related Content PubMed PubMed Citation Articles by Hoekstra, A. V. Articles by Kim, J. J. Related Collections Endocrine Oncology Female Endocrinology

Progestins Activate the AKT Pathway in Leiomyoma Cells and Promote Survival

Divisions of Gynecologic Oncology (A.V.H., E.B.), Reproductive Biology Research (E.C.S., Z.L., J.H., P.Y., D.C., S.B., J.K.), and Reproductive Endocrinology and Infertility (E.M., S.B.), Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois 60611; and Department of Biological Chemistry and Molecular Pharmacology (J.C.), Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: J. Julie Kim, Ph.D., Department of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, 303 East Superior, Room 4-117, Northwestern University, Chicago, Illinois 60611. E-mail: j-kim4{at}northwestern.edu.

Context: Progesterone has been associated with promoting growth of uterine leiomyomas. The mechanisms involved remain unclear.

Objective: In this study we investigated the activation of the AKT pathway and its downstream effectors, glycogen synthase kinase-3b and Forkhead box O (FOXO)-1 by progesterone as a mechanism of proliferation and survival of leiomyoma cells. Inhibitors of the AKT pathway were used to demonstrate the role of phosphatidylinositol 3-kinase, AKT, and FOXO1 in contributing to cell proliferation and apoptosis.

Results: Treatment of leiomyoma cells with R5020 over a period of 72 h resulted in higher cell numbers compared with untreated cells. When cells were treated with 100 nM R5020 for 1 and 24 h, the levels of phospho(Ser 473)-AKT increased. This increase was inhibited when cells were cotreated with RU486. Treatment of leiomyoma cells with a phosphatidylinositol 3-kinase inhibitor, LY294 dramatically decreased levels of phospho(Ser 473)-AKT, despite R5020 treatment. In addition to increased phospho(Ser 473)-AKT levels, R5020 treatment resulted in an increase in phospho(Ser 256)-FOXO1 and phosphoglycogen synthase kinase-3b. Inhibition of AKT using API-59 decreased proliferation and cell viability even in the presence of R5020. Higher concentrations of API-59-induced apoptosis of leiomyoma cells, even in the presence of R5020. Psammaplysene A increased nuclear FOXO1 levels and did not affect cell proliferation but induced apoptosis of leiomyoma cells.

Conclusions: The progestin, R5020, can rapidly activate the AKT pathway. Inhibition of the AKT pathway inhibits cell proliferation and promotes apoptosis of leiomyoma cells.