Activation of protein kinase B by WNT4 as a regulator of uterine leiomyoma stem cell function

Shimeng Liu, Ping Yin, Ariel J. Dotts, Stacy A. Kujawa, John S. Coon V, Jian Jun Wei, Debabrata Chakravarti, Serdar E. Bulun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Objective: To investigate the functional interaction between the Wnt/β-catenin and protein kinase B (Akt) pathways in leiomyoma stem cells (LSC). Design: Laboratory study. Setting: Research laboratory. Patient(s): Premenopausal women (n = 36; age range: 28 to 49 years) undergoing hysterectomy or myomectomy for leiomyoma. Intervention(s): None. Main Outcome Measure(s): Gene expression, protein phosphorylation, and cell proliferation. Result(s): Cells from human leiomyoma tissues were sorted by fluorescence-activated cell sorting (FACS) into three populations: LSC, intermediate cells (LIC), and differentiated cells (LDC) with the function of the Wnt/β-catenin and Akt signaling pathways in leiomyoma cells evaluated using real-time quantitative polymerase chain reaction and immunoblot analyses. The Wnt/β-catenin signaling pathway components were differentially expressed in each leiomyoma cell population. WNT4 was distinctly overexpressed in LIC, and its receptor FZD6 was primarily expressed in LSC. WNT4 stimulated Akt phosphorylation, activated β-catenin, and increased primary leiomyoma cell proliferation. These stimulatory effects were abolished by cotreatment with the Akt inhibitor, MK-2206. WNT4 up-regulated the expression of pro-proliferative genes, c-Myc and cyclin D1, specifically in LSC; this was also abrogated by Akt inhibition. Conclusion(s): Our data suggest that WNT4 regulates LSC proliferation via Akt-dependent β-catenin activation, representing a key step toward a better understanding of LSC regulation and potentially novel therapeutic targets.

Original languageEnglish (US)
JournalFertility and Sterility
DOIs
StateAccepted/In press - 2020

Keywords

  • Akt
  • Wnt/β-catenin
  • stem cell function
  • uterine leiomyoma

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Fingerprint Dive into the research topics of 'Activation of protein kinase B by WNT4 as a regulator of uterine leiomyoma stem cell function'. Together they form a unique fingerprint.

Cite this