Ciglitizone inhibits cell proliferation in human uterine leiomyoma via activation of store-operated Ca2+ channels.
This study investigated the acute effects of a peroxisome proliferator-activated receptor (PPAR)-gamma 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 microM) 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-gamma 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.
Kim
Byoung Ywong
BY
Department of Physiology, Keimyung University School of Medicine, Daegu, Korea.
Cho
Chi-Heum
CH
Song
Dae-Kyu
DK
Mun
Kyo-Cheol
KC
Suh
Seong-Il
SI
Kim
Sang-Pyo
SP
Shin
Dong-Hoon
DH
Jang
Byeong-Churl
BC
Kwon
Taeg Kyu
TK
Cha
Soon-Do
SD
Bae
Insoo
I
Bae
Jae Hoon
JH
D002118:Calcium / Q000032:analysis / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000737:chemistry / Q000378:metabolism; D007889:Leiomyoma / Q000378:metabolism*; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000378:metabolism*
D015220:Calcium Channels; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D045162:Thiazolidinediones; D002118:Calcium; C039671:ciglitazone