| Literature DB >> 24291004 |
Erich Piovan1,2,3, Jiyang Yu4,5, Valeria Tosello1,6, Daniel Herranz1, Alberto Ambesi-Impiombato1, Ana Carolina Da Silva1, Marta Sanchez-Martin1, Arianne Perez-Garcia1, Isaura Rigo1, Mireia Castillo7, Stefano Indraccolo2, Justin R Cross8, Elisa de Stanchina9, Elisabeth Paietta10,11, Janis Racevskis10,11, Jacob M Rowe12, Martin S Tallman13, Giuseppe Basso14, Jules P Meijerink15, Carlos Cordon-Cardo7, Andrea Califano1,4,5, Adolfo A Ferrando1,7,16.
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.Entities:
Mesh：
Substances：
Year: 2013 PMID： 24291004 PMCID： PMC3878658 DOI： 10.1016/j.ccr.2013.10.022
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743