Faculty Collaboration Database

Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. Leukemia 2009 Apr;23(4):784-90

Date

02/20/2009

Pubmed ID

19225536

DOI

10.1038/leu.2008.348

Scopus ID

2-s2.0-64849110053 (requires institutional sign-in at Scopus site)   64 Citations

Abstract

Mantle cell lymphoma (MCL) is a clinically aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) and overexpression of cyclin D1. A high proportion of MCL tumors harbor wild-type (wt) and potentially functional p53 gene. We show here that stabilization and activation of wt-p53 using a recently developed potent MDM2 inhibitor, nutlin 3A, results in significant p53-dependent G1-S cell cycle arrest and apoptosis in MCL cells through regulation of p53 target genes. As mTOR signaling is activated in MCL and may control cyclin D1 levels, we show that p53 activation may downregulate the AKT/mTOR pathway through a mechanism involving AMP kinase (AMPK). Despite the non-genotoxic mode of nutlin 3A treatment, we show evidence that stabilization of p53 is associated with its phosphorylation at serine 15 residue and activation of AMPK. Stimulation of AMPK kinase activity using AICAR inhibits phosphorylation of critical downstream effectors of mTOR signaling, such as 4E-BP1 and rpS6. Pharmacologic inhibition of AMPK using compound C in nutlin-3A-treated MCL cells harboring wt-p53 did not affect the level of (ser15)p-p53, suggesting that the (ser15)p-p53 --> AMPK is the direction involved in the p53/AMPK/mTOR cross talk. These data establish a p53 --> AMPK --> mTOR mechanism in MCL and uncover a novel biologic effect of potent MDM2 inhibitors in preclinical models of MCL.

Author List

Drakos E, Atsaves V, Li J, Leventaki V, Andreeff M, Medeiros LJ, Rassidakis GZ

MESH terms used to index this publication - Major topics in bold

Apoptosis
Down-Regulation
Imidazoles
Lymphoma, Mantle-Cell
Phosphorylation
Piperazines
Protein Kinases
Protein Stability
Proto-Oncogene Proteins c-mdm2
Receptor Cross-Talk
Signal Transduction
TOR Serine-Threonine Kinases
Tumor Cells, Cultured
Tumor Suppressor Protein p53