Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2013 Dec 3

PMID 24291004

Citations 149

Authors

Erich Piovan

Jiyang Yu

Valeria Tosello

Daniel Herranz

Alberto Ambesi-Impiombato

Ana Carolina da Silva

Marta Sanchez-Martin

Arianne Perez-Garcia

Isaura Rigo

Mireia Castillo

Stefano Indraccolo

Justin R Cross

Elisa de Stanchina

Elisabeth Paietta

Janis Racevskis

Jacob M Rowe

Martin S Tallman

Giuseppe Basso

Jules P Meijerink

Carlos Cordon-Cardo

Andrea Califano

Adolfo A Ferrando

Affiliations

Soon will be listed here.

Abstract

Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.

Citing Articles

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