Rapamycin Inhibits IGF-1-Mediated Up-Regulation of MDM2 and Sensitizes Cancer Cells to Chemotherapy |
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| Authors: | Wei Du Yong Yi Haibo Zhang Johann Bergholz Junfeng Wu Haoqiang Ying Yujun Zhang Zhi-Xiong Jim Xiao |
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| Institution: | 1. Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.; 2. Center of Growth, Metabolism and Aging, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.; 3. The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.; University of Texas Health Science Center at San Antonio/Greehey CCRI, United States of America, |
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| Abstract: | The Murine Double Minute 2 (MDM2) protein is a key regulator of cell proliferation and apoptosis that acts primarily by inhibiting the p53 tumor suppressor. Similarly, the PI3-Kinase (PI3K)/AKT pathway is critical for growth factor-mediated cell survival. Additionally, it has been reported that AKT can directly phosphorylate and activate MDM2. In this study, we show that IGF-1 up-regulates MDM2 protein levels in a PI3K/AKT-dependent manner. Inhibition of mTOR by rapamycin or expression of a dominant negative eukaryotic initiation factor 4E binding protein 1 (4EBP1) mutant protein, as well as ablation of eukaryotic initiation factor 4E (eIF4E), efficiently abolishes IGF-1-mediated up-regulation of MDM2. In addition, we show that rapamycin effectively inhibits MDM2 expression and sensitizes cancer cells to chemotherapy. Taken together, this study reveals a novel mechanism by which IGF-1 activates MDM2 via the mTOR pathway, and that pharmacologic inhibition of mTOR combined with chemotherapy may be more effective in treatment of a subset of cancers harboring increased MDM2 activation. |
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