Myeloid Cell Leukemia-1 Inversely Correlates with Glycogen
Synthase Kinase-3B Activity and Associates with Poor Prognosis in Human Breast Cancer

Qingqing Ding,1 Xianghuo He,1,5 Weiya Xia,1 Jung-Mao Hsu,1,2 Chun-Te Chen,1 Long-Yuan Li,1,3,4
Dung-Fang Lee,1,2 Jer-Yen Yang,1,2 Xiaoming Xie,1 Jaw-Ching Liu,1 and Mien-Chie Hung1,2,3,4
1Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center; 2Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas; 3Center for Molecular Medicine, China Medical University Hospital; 4Asia University, Taichung, Taiwan; and 5State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai, China

Abstract
Myeloid cell leukemia-1 (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-3B (GSK-3B), a key component of the Wnt signaling pathway, is involved in multiple physiologic processes such as protein synthesis, tumorigenesis, and apoptosis. Here, we report that expression of Mcl-1 was correlated with phosphorylated GSK-3B (p-GSK-3B) at Ser9 (an inactivated form of GSK-3B) 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-3B could down-regulate Mcl-1 and was
required for proteasome-mediated Mcl-1 degradation. Under some physiologic conditions, such as UV irradiation, anticancer drug treatment, and inhibition of growth factor pathways, Mcl-1 was down-regulated through activation of GSK-3B. Our results indicate that Mcl-1 stabilization by GSK-3B inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer.
[Cancer Res 2007;67(10):4564–71]