title: Rapamycin inhibits IGF-1-mediated up-regulation of MDM2 and sensitizes cancer cells to chemotherapy.
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.
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Wei
authors: W
authors: Du
authors: Yong
authors: Y
authors: Yi
authors: Haibo
authors: H
authors: Zhang
authors: Johann
authors: J
authors: Bergholz
authors: Junfeng
authors: J
authors: Wu
authors: Haoqiang
authors: H
authors: Ying
authors: Yujun
authors: Y
authors: Zhang
authors: Zhi-Xiong Jim
authors: ZX
authors: Xiao
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051736:Proto-Oncogene Proteins c-mdm2; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases
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