Afrin, Sadia, El Sabeh, Malak, Islam, Md Soriful, Miyashita-Ishiwata, Mariko, Malik, Minnie, Catherino, William H., Akimzhanov, Askar M., Boehning, Darren, Yang, Qiwei, Al-Hendy, Ayman, Segars, James H., and Borahay, Mostafa A.
Uterine leiomyomas or fibroids are the most common tumors of the female reproductive tract. Estrogen (E 2), 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 E 2 -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 E 2 downstream signaling, including ERK and AKT pathways, E 2 /ER transcriptional activity and E 2 -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 E 2 /ER signaling targets with potential implications in leiomyoma therapy and beyond. [Display omitted] • Simvastatin, an anti-hyperlipidemic drug, can prevent the growth of uterine leiomyoma in vitro and in vivo. • Simvastatin reduces E2-mediated signaling, including ERK and AKT pathways, and ESR1 transcriptional activity. • Treatment alters E2 receptor trafficking by reducing ER-α palmitoylation and increasing ubiquitin-mediated ER-α degradation. • Simvastatin reduced ER-α expression in leiomyoma mouse model and clinical samples, promising possible therapeutic potential. [ABSTRACT FROM AUTHOR]