Ciglitizone inhibits cell proliferation in human uterine leiomyoma via activation of store-operated Ca2+ channels |
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Authors: | Kim Byoung Ywong Cho Chi-Heum Song Dae-Kyu Mun Kyo-Cheol Suh Seong-Il Kim Sang-Pyo Shin Dong-Hoon Jang Byeong-Churl Kwon Taeg Kyu Cha Soon-Do Bae Insoo Bae Jae Hoon |
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Institution: | Department of Physiology, Keimyung University School of Medicine, Daegu, Korea. |
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Abstract: | This study investigated the acute effects of a peroxisome proliferator-activated receptor (PPAR)- ligand, ciglitizone, on cell proliferation and intracellular Ca2+ signaling in human normal myometrium and uterine leiomyoma. Changes in intracellular Ca2+ concentration (Ca2+]i) were measured with fura-2 AM, and cellular viabilities were determined by viable cell count and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction assay. Ciglitizone (100 µM) induced greater inhibition of cell proliferation in uterine leiomyoma than in myometrium. Ciglitizone also dose-dependently increased Ca2+]i in both myometrium and uterine leiomyoma; these Ca2+]i increases were inhibited by PPAR- antagonists and raloxifene. Ciglitizone-induced Ca2+]i increase showed only an initial peak in normal myometrial cells, whereas in uterine leiomyoma there was a second sustained Ca2+]i increase as well. The initial Ca2+]i increase in both myometrium and uterine leiomyoma resulted from the release of Ca2+ by the sarcoplasmic reticulum via activation of ryanodine receptors. The second Ca2+]i increase was observed only in uterine leiomyoma because of a Ca2+ influx via an activation of store-operated Ca2+ channels (SOCCs). Cell proliferation was inhibited and secondary Ca2+]i increase in uterine leiomyoma was attenuated by cotreatment of ciglitizone with a SOCC blocker, lanthanum. The results suggest that ciglitizone inhibits cell proliferation and increases Ca2+]i through the activation of SOCCs, especially in human uterine leiomyoma. peroxisome proliferator-activated receptor-; intracellular calcium; uterine cells |
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