Glycogen Synthase Kinase 3β Inhibition as a Therapeutic Approach in the Treatment of Endometrial Cancer

International Journal of Molecular Sciences

Yan Yin³  Nora T. Kizer²  Premal H. Thaker²  Katherine B. Chiappinelli¹  Kathryn M. Trinkaus⁴  Paul J. Goodfellow² 

[1] Division of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, MO 63110, USA; E-Mail:;Department of Obstetrics and Gynecology, Washington University School of Medicine, 660 South Euclid Avenue, MO 63110, USA; E-Mails:;Division of Dermatology, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, MO 63110, USA; E-Mail:;Division of Biostatistics, Washington University School of Medicine, 660 South Euclid Avenue, MO 63110, USA; E-Mail:

关键词: lithium chloride;    GSK3β;    endometrial cancer;   

DOI  :  10.3390/ijms140816617

来源: mdpi

【 摘 要 】

Alternative strategies beyond current chemotherapy and radiation therapy regimens are needed in the treatment of advanced stage and recurrent endometrial cancers. There is considerable promise for biologic agents targeting the extracellular signal-regulated kinase (ERK) pathway for treatment of these cancers. Many downstream substrates of the ERK signaling pathway, such as glycogen synthase kinase 3β (GSK3β), and their roles in endometrial carcinogenesis have not yet been investigated. In this study, we tested the importance of GSK3β inhibition in endometrial cancer cell lines and in vivo models. Inhibition of GSK3β by either lithium chloride (LiCl) or specific GSK3β inhibitor VIII showed cytostatic and cytotoxic effects on multiple endometrial cancer cell lines, with little effect on the immortalized normal endometrial cell line. Flow cytometry and immunofluorescence revealed a G2/M cell cycle arrest in both type I (AN3CA, KLE, and RL952) and type II (ARK1) endometrial cancer cell lines. In addition, LiCl pre-treatment sensitized AN3CA cells to the chemotherapy agent paclitaxel. Administration of LiCl to AN3CA tumor-bearing mice resulted in partial or complete regression of some tumors. Thus, GSK3β activity is associated with endometrial cancer tumorigenesis and its pharmacologic inhibition reduces cell proliferation and tumor growth.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland