Phosphorylation of glycogen synthase kinase-3 β 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 β (GSK-3β) is a multi-functional serine/threonine kinase. Its activity is regulated
negatively by the phosphorylation of serine 9 (pGSK-3β-ser-9) and positively by the phosphorylation of tyrosine 216 (pGSK-3β-tyr-216). We compared the expression/phosphorylation of GSK-3β between the cisplatin-sensitive ovarian carcinoma cell line A2780 and its cisplatin-resistant
derivative CP70. The expression levels of total GSK-3β and pGSK-3β-tyr-216 were similar in these cells; however, CP70 cells had a much higher expression of pGSK-3β-ser-9 than A2780 cells. Lithium chloride, which is a GSK-3β inhibitor and stimulates pGSK-3β-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-3β 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-3β negatively regulated the expression of p53. Therefore, pGSK-3β-ser-9 may confer the cisplatin resistance of ovarian carcinomas through the stabilization of p53
expression. Our study establishes a potential role of GSK-3β in the development of cisplatin resistance in initially sensitive tumors.
Document Type: Research Article
Affiliations: Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medicine University, Xi'an, Shanghai 710032, P.R. China
Publication date: 01 January 2007
- The International Journal of Oncology provides an international forum for the publication of the latest, cutting-edge research in the broad area of oncology and cancer treatment. The journal accepts original high quality works and reviews on all aspects of oncology research including carcinogenesis, metastasis, epidemiology, chemotherapy and viral oncology. Through fair and efficient peer review, the journal is dedicated to publishing top tier research in the field, offering authors rapid publication as well as high standards of copy-editing and production. The International Journal of Oncology is published on a monthly basis in both print and early online.
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