A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells

J Clin Endocrinol Metab. 2019 Mar 1;104(3):970-980. doi: 10.1210/jc.2018-01216.


Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood.

Objective: Our prior studies revealed that A-kinase anchoring protein 13 (AKAP13) was overexpressed in fibroids and contributed to altered mechanotransduction in fibroids. Because AKAP13 augmented nuclear receptor signaling in other tissues, we sought to determine whether AKAP13 might influence PR signaling in fibroids.

Methods and results: Fibroid samples from patients treated with ulipristal acetate or placebo were examined for AKAP13 expression by using immunohistochemistry. In immortalized uterine fibroid cell lines and COS-7 cells, we observed that AKAP13 increased ligand-dependent PR activation of luciferase reporters and endogenous progesterone-responsive genes for PR-B but not PR-A. Inhibition of ERK reduced activation of PR-dependent signaling by AKAP13, but inhibition of p38 MAPK had no effect. In addition, glutathione S-transferase‒binding assays revealed that AKAP13 was bound to PR-B through its carboxyl terminus.

Conclusion: These data suggest an intersection of mechanical signaling and PR signaling involving AKAP13 through ERK. Further elucidation of the integration of mechanical and hormonal signaling pathways in fibroids may provide insight into fibroid development and suggest new therapeutic strategies for treatment.

Trial registration: ClinicalTrials.gov NCT00290251.

Publication types

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

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Adult
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Leiomyoma / drug therapy
  • Leiomyoma / pathology*
  • MAP Kinase Signaling System / drug effects
  • Mechanotransduction, Cellular / drug effects
  • Middle Aged
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism*
  • Norpregnadienes / pharmacology
  • Norpregnadienes / therapeutic use
  • Progesterone / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Small Interfering / metabolism
  • Receptors, Progesterone / antagonists & inhibitors
  • Receptors, Progesterone / metabolism*
  • Uterine Neoplasms / drug therapy
  • Uterine Neoplasms / pathology*
  • Uterus / drug effects
  • Uterus / pathology


  • A Kinase Anchor Proteins
  • AKAP13 protein, human
  • Minor Histocompatibility Antigens
  • Norpregnadienes
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Receptors, Progesterone
  • Progesterone
  • ulipristal acetate

Associated data

  • ClinicalTrials.gov/NCT00290251