A selective serotonin 5-HT1B receptor inhibition suppresses cells proliferation and induces apoptosis in human uterine leiomyoma cells

Nilgun Gurbuz; Mehmet Resit Asoglu; Ahmed A Ashour; Salama Salama; Gokhan S Kilic; Bulent Ozpolat

doi:10.1016/j.ejogrb.2016.08.006

A selective serotonin 5-HT_1B receptor inhibition suppresses cells proliferation and induces apoptosis in human uterine leiomyoma cells

Eur J Obstet Gynecol Reprod Biol. 2016 Nov:206:114-119. doi: 10.1016/j.ejogrb.2016.08.006. Epub 2016 Aug 10.

Authors

Nilgun Gurbuz¹, Mehmet Resit Asoglu², Ahmed A Ashour¹, Salama Salama³, Gokhan S Kilic⁴, Bulent Ozpolat⁵

Affiliations

¹ Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA.
² Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
³ Baylor College of Medicine, Department of Obstetrics and Gynecology, Houston, TX, USA.
⁴ Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
⁵ Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: Bozpolat@mdanderson.org.

PMID: 27669395
DOI: 10.1016/j.ejogrb.2016.08.006

Abstract

Objective: Uterine leiomyomas (fibroids or myomas) are the most common pelvic tumor in women with about 70% lifetime incidence rate. Currently, the only definitive treatment is surgery, causing undesirable side effects and negative impact on women's quality of life, reproductive ability, and a substantial impact on healthcare costs. Therefore, curative medical treatments are needed to be developed. In this study, we investigated the impact of serotonin receptor 5-HT_1B on cell proliferation and survival in human uterine leiomyoma cells (huLM).

Study design: The impact of 5-HT_1B receptor on cell proliferation, survival and apoptosis was investigated using a selective 5-HTR_1B antagonist SB216641 in huLM cells, utilizing MTS, colony formation assay and Annexin V staining, respectively. Mechanisms of inhibition of cell proliferation, survival and induction of apoptosis were investigated by Western blot analysis after treatment with various doses of HT_1B antagonist.

Results: 5-HT_1B receptor inhibition leads to a significant decrease in proliferation and colony formation in huLM cells, reduction of cyclin D1 and alpha-smooth muscle actin (α-SMA) expressions and the activity of Mitogen Activated Protein Kinase (MAPK) ERK and Elongation Factor 2 kinase (EF2K) pathways. 5-HT_1B receptor blockage also induces apoptotic cell death by inducing cleavage of caspase-8, -9, and -3 and PARP.

Conclusion: Our findings show for the first time that 5-HT_1B receptor promotes uterine leiomyoma cell survival and proliferation and its inhibition may be a potential therapeutic approach for human uterine leiomyomas. Thus, 5-HT_1B expression and antagonists should be further investigated in leiomyoma tumors.

Keywords: 5-HT(1B); 5-Hydroxytriptamine; Antagonist; Apoptosis; Cyclin D1; EF2K; ERK; Fibroid; MAPK; Myoma; Proliferation; Receptor; SB216641; Serotonin; Survival; Treatment; Uterine leiomyoma.

MeSH terms

Apoptosis / drug effects*
Benzamides / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects*
Cell Survival / drug effects
Female
Humans
Leiomyoma / pathology*
Oxadiazoles / pharmacology*
Serotonin 5-HT1 Receptor Antagonists / pharmacology*
Signal Transduction / drug effects
Uterine Neoplasms / pathology*

Substances

Benzamides
N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide
Oxadiazoles
Serotonin 5-HT1 Receptor Antagonists