Progestins activate the AKT pathway in leiomyoma cells and promote survival.

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, 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.

• Authors: Anna V Hoekstra, Elizabeth C Sefton, Emily Berry, Zhenxiao Lu, Jennifer Hardt, Erica Marsh, Ping Yin, Jon Clardy, Debabrata Chakravarti, Serdar Bulun, J Julie Kim
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 94 Issue 5 Pg. 1768-74 (May 2009) ISSN: 1945-7197 [Electronic] United States
• PMID: 19240153 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Progestins
• Mifepristone
• Promegestone
• Oncogene Protein v-akt

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Fluorescent Antibody Technique
• Forkhead Box Protein O1
• Forkhead Transcription Factors (genetics)
• Humans
• Leiomyoma (pathology)
• Mifepristone (pharmacology)
• Oncogene Protein v-akt (metabolism, physiology)
• Phosphorylation
• Progestins (pharmacology)
• Promegestone (pharmacology)
• Signal Transduction (drug effects)
• Uterine Neoplasms (pathology)