Year: 2009
Type: article
Abstract: ABSTRACT 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, GSK3b and FOXO1 by progesterone as a mechanism of proliferation and survival of leiomyoma cells. Inhibitors of the AKT pathway were used to demonstrate the role of PI3K, AKT and FOXO1 in contributing to cell proliferation and apoptosis. Results Treatment of leiomyoma cells with R5020 over a period of 72h resulted in higher cell numbers compared to untreated cells. When cells were treated with 100nM R5020 for 1h and 24h, the levels of phospho(Ser 473)-AKT increased. This increase was inhibited when cells were co-treated with RU486. Treatment of leiomyoma cells with a PI3K 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 phospho-GSK3b. 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.
Source: Molecular Endocrinology
Language: English
Subfield: Obstetrics and Gynecology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3211472834