Format

Send to

Choose Destination
See comment in PubMed Commons below
Cancer Cell. 2013 Dec 9;24(6):766-76. doi: 10.1016/j.ccr.2013.10.022. Epub 2013 Nov 27.

Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
2
UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, 35128, Italy.
3
Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita' di Padova, Padova, Padova, Veneto, 35128, Italy.
4
Department of Biomedical Informatics, Columbia University, New York, NY, 10032, USA.
5
Department of Systems Biology, Columbia University, New York, NY, 10032, USA.
6
Istituto Oncologico Veneto, IRCCS, Padova, Veneto, 35128, Italy.
7
Department of Pathology, Mount Sinai School of Medicine, New York, NY, 10029, USA.
8
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065 USA.
9
Antitumor Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065 USA.
10
Department of Medicine, Albert Einstein School of Medicine, Bronx, NY, 10461, USA.
11
New York Medical College and Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
12
Hematology Department, Shaare Zedek Hospital, Jerusalem, 91031, Israel.
13
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
14
Dipartimento di Salute della Donna e del Bambino, Università di Padova, via Giustiniani 3, 35128, Padova, Italy.
15
Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, South Holland, 010 7040704, the Netherlands.
16
Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
#
Contributed equally

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.

PMID:
24291004
PMCID:
PMC3878658
DOI:
10.1016/j.ccr.2013.10.022
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for PubMed Central
    Loading ...
    Support Center