Journal
CANCER CELL
Volume 24, Issue 6, Pages 766-776Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2013.10.022
Keywords
-
Categories
Funding
- National Institutes of Health [R01CA129382, U24 CA114737, RC2 CA148308, U54CA121852]
- Stand Up To Cancer Innovative Research Award
- Chemotherapy Foundation
- Leukemia & Lymphoma Society Scholar Award
- Leukemia & Lymphoma Society SCOR Grant
- ECOG Leukemia Tissue Bank
Ask authors/readers for more resources
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 glubocorticoid 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available