Rapamycin Inhibits IGF-1-Mediated Up-Regulation of MDM2 and Sensitizes Cancer Cells to Chemotherapy

10Citations
Citations of this article
14Readers
Mendeley users who have this article in their library.

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. © 2013 Du et al.

Cite

CITATION STYLE

APA

Du, W., Yi, Y., Zhang, H., Bergholz, J., Wu, J., Ying, H., … Xiao, Z. X. J. (2013). Rapamycin Inhibits IGF-1-Mediated Up-Regulation of MDM2 and Sensitizes Cancer Cells to Chemotherapy. PLoS ONE, 8(4). https://doi.org/10.1371/journal.pone.0063179

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free