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Int. J. Mol. Sci. 2013, 14(8), 16617-16637; doi:10.3390/ijms140816617
Article

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

1,†
, 2,†
, 2
, 3
, 4
, 2
 and 1,5,*
Received: 17 May 2013; in revised form: 19 July 2013 / Accepted: 24 July 2013 / Published: 12 August 2013
(This article belongs to the Special Issue Molecular Research of Carcinogenesis)
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Abstract: 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.
Keywords: lithium chloride; GSK3β; endometrial cancer lithium chloride; GSK3β; endometrial cancer
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Yin, Y.; Kizer, N.T.; Thaker, P.H.; Chiappinelli, K.B.; Trinkaus, K.M.; Goodfellow, P.J.; Ma, L. Glycogen Synthase Kinase 3β Inhibition as a Therapeutic Approach in the Treatment of Endometrial Cancer. Int. J. Mol. Sci. 2013, 14, 16617-16637.

AMA Style

Yin Y, Kizer NT, Thaker PH, Chiappinelli KB, Trinkaus KM, Goodfellow PJ, Ma L. Glycogen Synthase Kinase 3β Inhibition as a Therapeutic Approach in the Treatment of Endometrial Cancer. International Journal of Molecular Sciences. 2013; 14(8):16617-16637.

Chicago/Turabian Style

Yin, Yan; Kizer, Nora T.; Thaker, Premal H.; Chiappinelli, Katherine B.; Trinkaus, Kathryn M.; Goodfellow, Paul J.; Ma, Liang. 2013. "Glycogen Synthase Kinase 3β Inhibition as a Therapeutic Approach in the Treatment of Endometrial Cancer." Int. J. Mol. Sci. 14, no. 8: 16617-16637.



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