Progestins Activate the AKT Pathway in Leiomyoma Cells and Promote Survival

J Clin Endocrinol Metab. 2009 May;94(5):1768-74. doi: 10.1210/jc.2008-2093. Epub 2009 Feb 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Oncogene Protein v-akt / physiology*
  • Phosphorylation
  • Progestins / pharmacology*
  • Promegestone / pharmacology
  • Signal Transduction / drug effects*
  • Uterine Neoplasms / pathology*

Substances

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