Uterine
leiomyomas or
fibroids are the most common
tumors of the female reproductive tract.
Estrogen (E2), a
steroid-derived
hormone, and its receptors (ERs), particularly ER-α, are important drivers for the development and growth of
leiomyomas. We previously demonstrated that
simvastatin, a
drug used for
hyperlipidemia, also possesses anti-
leiomyoma properties. The aim of this work is to investigate the impact of
simvastatin on ER-α signaling in
leiomyoma cells, including its expression, downstream signaling, transcriptional activity, post-translational modification, trafficking and degradation. Primary and immortalized human uterine
leiomyoma (HuLM) cells were used for in vitro experiments. Immunodeficient mice xenografted with human
leiomyoma tissue explants were used for in vivo studies.
Leiomyoma samples were obtained from patients enrolled in an ongoing double-blinded, phase II, randomized controlled trial. Here, we found that
simvastatin significantly reduced E2-induced proliferation and
PCNA expression. In addition,
simvastatin reduced total ER-α expression in
leiomyoma cells and altered its subcellular localization by inhibiting its trafficking to the plasma membrane and nucleus.
Simvastatin also inhibited E2 downstream signaling, including ERK and AKT pathways, E2/ER transcriptional activity and E2-responsive genes. To explain
simvastatin effects on ER-α level and trafficking, we examined its effects on ER-α post-translational processing. We noticed that
simvastatin reduced ER-α palmitoylation; a required modification for its stability, trafficking to plasma membrane, and signaling. We also observed an increase in
ubiquitin-mediated ER-α degradation. Importantly, we found that the effects of
simvastatin on ER-α expression were recapitulated in the xenograft
leiomyoma mouse model and human tissues. Thus, our data suggest that
simvastatin modulates several E2/ER signaling targets with potential implications in
leiomyoma therapy and beyond.