Inhibition of canonical WNT signaling attenuates human leiomyoma cell growth

Capsule:
Small molecules that specifically inhibit the canonical WNT/b-catenin pathway attenuate growth and proliferation of human uterine leiomyoma cell primary cultures.

Authors:
Masanori Ono, M.D., Ph.D., Ping Yin, Ph.D., Antonia Navarro, M.Sc., Molly B. Moravek, M.D., John S. Coon, M.Sc., Stacy A. Druschitz, B.Sc., Cara J. Gottardi, Ph.D., Serdar E. Bulun, M.D.

Volume 101, Issue 5, Pages 1441–1449.e1

Abstract:

Objective:
To assess the effect of three WNT/β-catenin pathway inhibitors—inhibitor of β-catenin and TCF4 (ICAT), niclosamide, and XAV939—on the proliferation of primary cultures of human uterine leiomyoma cells.

Design:
Prospective study of human leiomyoma cells obtained from myomectomy or hysterectomy.

Setting:
University research laboratory.

Patient(s):
Women (n = 38) aged 27–53 years undergoing surgery.

Intervention(s):
Adenoviral ICAT overexpression or treatment with varying concentrations of niclosamide or XAV939.

Main Outcome Measure(s):
Cell proliferation, cell death, WNT/-catenin target gene expression or reporter gene regulation, β-catenin levels, and cellular localization.

Result(s):
Inhibitor of β-catenin and TCF4, niclosamide, or XAV939 inhibit WNT/β-catenin pathway activation and exert antiproliferative effects in primary cultures of human leiomyoma cells.

Conclusion(s):
Three WNT/-catenin pathway inhibitors specifically block human leiomyoma growth and proliferation, suggesting that the canonical WNT pathway may be a potential therapeutic target for the treatment of uterine leiomyoma. Our findings provide rationale for further preclinical and clinical evaluation of ICAT, niclosamide, and XAV939 as candidate antitumor agents for uterine leiomyoma.

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