A selective serotonin 5-HT1Breceptor inhibition suppresses cells proliferation and induces apoptosis in human uterine leiomyoma cells.
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-HT1Bon cell proliferation and survival in human uterine leiomyoma cells (huLM).


METHODS
The impact of 5-HT1Breceptor on cell proliferation, survival and apoptosis was investigated using a selective 5-HTR1Bantagonist 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 HT1Bantagonist.


RESULTS
5-HT1Breceptor 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-HT1Breceptor blockage also induces apoptotic cell death by inducing cleavage of caspase-8, -9, and -3 and PARP.


CONCLUSIONS
Our findings show for the first time that 5-HT1Breceptor promotes uterine leiomyoma cell survival and proliferation and its inhibition may be a potential therapeutic approach for human uterine leiomyomas. Thus, 5-HT1Bexpression and antagonists should be further investigated in leiomyoma tumors.
Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA.
Nilgun
N
Gurbuz
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.
Mehmet Resit
MR
Asoglu
Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA.
Ahmed A
AA
Ashour
Baylor College of Medicine, Department of Obstetrics and Gynecology, Houston, TX, USA.
Salama
S
Salama
Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX 77555, USA.
Gokhan S
GS
Kilic
Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: Bozpolat@mdanderson.org.
Bulent
B
Ozpolat
D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000473:pathology*; D010069:Oxadiazoles / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014594:Uterine Neoplasms / Q000473:pathology*
D001549:Benzamides; C108531:N-(3-(2-dimethylamino)ethoxy-4-methoxyphenyl)-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide; D010069:Oxadiazoles; D058829:Serotonin 5-HT1 Receptor Antagonists
5-HT(1B); 5-Hydroxytriptamine; Antagonist; Apoptosis; Cyclin D1; EF2K; ERK; Fibroid; MAPK; Myoma; Proliferation; Receptor; SB216641; Serotonin; Survival; Treatment; Uterine leiomyoma