Mcl-1 inversely correlates with GSK-3β activity and associates with poor prognosis in human breast cancer

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Mcl-1 inversely correlates with GSK-3β activity and associates with poor prognosis in human breast cancer

Qingqing Ding, Xianghuo He, Weiya Xia, Jung-Mao Hsu, Chun-Te Chen, Long-Yuan Li, Dung-Fang Lee, Jaw-Ching Liu, and Mien-Chie Hung

Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

Mcl-1, an antiapoptotic Bcl-2 family member, is overexpressed in many types of human cancer, and associates with cell immortalization, malignant transformation and chemoresistance. Glycogen synthase kinase-3β (GSK-3β), a key component of the Wnt signaling pathway, is involved in multiple physiological processes such as protein synthesis, tumorigenesis and apoptosis. Here, we report that expression of Mcl-1 was correlated with phosphorylated GSK-3β at Ser 9 (an inactivated form of GSK-3β) in multiple cancer cell lines and primary human cancer samples. In addition, Mcl-1 was strikingly linked with poor prognosis of human breast cancer, in which the high level of Mcl-1 was related to high tumor grade and poor survival of breast cancer patients. Furthermore, we found that activation of GSK-3β could downregulate Mcl-1 and was required for proteasome-mediated Mcl-1 degradation. Under some physiological conditions, such as UV irradiation, anticancer drug treatment and inhibition of growth factor pathways, Mcl-1 was downregulated through activation of GSK-3β. Our results indicate that Mcl-1 stabilization by GSK-3β inactivation could be involved in tumorigenesis, and serve as a useful prognostic marker for human breast cancer.