Journal article
Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells
International journal of oncology, Vol.31(3), pp.657-662
09/2007
DOI: 10.3892/ijo.31.3.657
PMID: 17671694
Abstract
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.
Details
- Title: Subtitle
- Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells
- Creators
- Guoqing Cai - Xijing HospitalJian WangXiaoyan XinZunji KeJia Luo
- Resource Type
- Journal article
- Publication Details
- International journal of oncology, Vol.31(3), pp.657-662
- DOI
- 10.3892/ijo.31.3.657
- PMID
- 17671694
- NLM abbreviation
- Int J Oncol
- ISSN
- 1019-6439
- eISSN
- 1791-2423
- Grant note
- AA015407 / NIAAA NIH HHS
- Language
- English
- Date published
- 09/2007
- Academic Unit
- Pathology
- Record Identifier
- 9984186554902771
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