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.
Highlights
Abnormal activation of Murine Double Minute 2 (MDM2) has been established as an important causative factor in human cancer development
insulin-like growth factor 1 (IGF-1) induced MDM2 protein expression, as shown by an increase of both MDM2 protein bands detected by an MDM2-specific antibody, SMP14, consistent with previous reports [6,9,25]
This effect of IGF-1 on MDM2 was effectively blocked by treatment with LY294002, a selective PI3K inhibitor [26], but not by PD98059, an inhibitor of MAP kinase kinase (MEK), or by SB203580, a specific inhibitor of p38 stress-activated protein kinase [27]
Summary
Abnormal activation of Murine Double Minute 2 (MDM2) has been established as an important causative factor in human cancer development. MDM2 functions as an ubiquitin E3 ligase to facilitate degradation of p53, a key regulator for cell proliferation, apoptosis and senescence in response to cellular stresses, such as DNA damage and oncogenic stress [1]. Amplification of the MDM2 gene has been observed in a variety of human tumors and cancers, including soft tissue tumors, osteosarcoma, and esophageal carcinoma [2]. MDM2 has been shown to complex with and regulate protein stability and/or activity of a subset of proteins involved in cell proliferation and cell death, including p73 [10,11], E2F1 [12], cyclin-dependent kinase inhibitor p21 [13], betaarrestin, and G-protein-coupled receptor kinase 2 (GRK2) [14,15]
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