Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells.
Cisplatin is commonly used in the treatment of advanced ovarian carcinoma. A major limitation of the use of cisplatin is the development of resistance in tumors. Glycogen synthase kinase-3 beta (GSK-3beta) is a multi-functional serine/threonine kinase. Its activity is regulated negatively by the phosphorylation of serine 9 (pGSK-3beta-ser-9) and positively by the phosphorylation of tyrosine 216 (pGSK-3beta-tyr-216). We compared the expression/phosphorylation of GSK-3beta between the cisplatin-sensitive ovarian carcinoma cell line A2780 and its cisplatin-resistant derivative CP70. The expression levels of total GSK-3beta and pGSK-3beta-tyr-216 were similar in these cells; however, CP70 cells had a much higher expression of pGSK-3beta-ser-9 than A2780 cells. Lithium chloride, which is a GSK-3beta inhibitor and stimulates pGSK-3beta-ser-9, significantly increased the IC50 of cisplatin and counteracted cisplatin-induced apoptosis of A2780 and CP70 cells. In contrast, overexpression of a constitutively active S9A GSK-3beta mutant increased the sensitivity of CP70 cells to cisplatin and significantly enhanced cisplatin-mediated apoptosis. It is suggested that the cisplatin-resistance of CP70 cells is mediated by stabilizing p53. We demonstrated that GSK-3beta negatively regulated the expression of p53. Therefore, pGSK-3beta-ser-9 may confer the cisplatin resistance of ovarian carcinomas through the stabilization of p53 expression. Our study establishes a potential role of GSK-3beta in the development of cisplatin resistance in initially sensitive tumors.
Cai
Guoqing
G
Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medicine University, Xi'an, Shanghai, PR China.
Wang
Jian
J
Xin
Xiaoyan
X
Ke
Zunji
Z
Luo
Jia
J
D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D010766:Phosphorylation; D012694:Serine / Q000737:chemistry*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014443:Tyrosine; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D002945:Cisplatin