Ciglitizone inhibits cell proliferation in human uterine leiomyoma via activation of store-operated Ca2+ channels

1 Department of Physiology, 2 Department of Obstetrics and Gynecology, and 3 Chronic Disease Research Center, Keimyung University School of Medicine, Daegu, Korea; and 4 Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, District of Columbia Submitted 23 March 2004 ; accepted in final form 28 September 2004 This study investigated the acute effects of a peroxisome proliferator-activated receptor (PPAR)- ligand, ciglitizone, on cell proliferation and intracellular Ca 2+ signaling in human normal myometrium and uterine leiomyoma. Changes in intracellular Ca 2+ concentration ([Ca 2+ ] 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 [Ca 2+ ] i in both myometrium and uterine leiomyoma; these [Ca 2+ ] i increases were inhibited by PPAR- antagonists and raloxifene. Ciglitizone-induced [Ca 2+ ] i increase showed only an initial peak in normal myometrial cells, whereas in uterine leiomyoma there was a second sustained [Ca 2+ ] i increase as well. The initial [Ca 2+ ] i increase in both myometrium and uterine leiomyoma resulted from the release of Ca 2+ by the sarcoplasmic reticulum via activation of ryanodine receptors. The second [Ca 2+ ] i increase was observed only in uterine leiomyoma because of a Ca 2+ influx via an activation of store-operated Ca 2+ channels (SOCCs). Cell proliferation was inhibited and secondary [Ca 2+ ] 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 [Ca 2+ ] i through the activation of SOCCs, especially in human uterine leiomyoma. peroxisome proliferator-activated receptor- ; intracellular calcium; uterine cells Address for reprint requests and other correspondence: J. H. Bae, Dept. of Physiology, Keimyung Univ. School of Medicine, 194 Dongsan-Dong, Choong-Gu, Daegu, 700-712, Korea (E-mail: jhbae{at}dsmc.or.kr )