TY - JOUR
T1 - Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia
AU - Piovan, Erich
AU - Yu, Jiyang
AU - Tosello, Valeria
AU - Herranz, Daniel
AU - Ambesi-Impiombato, Alberto
AU - DaSilva, Ana Carolina
AU - Sanchez-Martin, Marta
AU - Perez-Garcia, Arianne
AU - Rigo, Isaura
AU - Castillo, Mireia
AU - Indraccolo, Stefano
AU - Cross, Justin R.
AU - deStanchina, Elisa
AU - Paietta, Elisabeth
AU - Racevskis, Janis
AU - Rowe, Jacob M.
AU - Tallman, Martin S.
AU - Basso, Giuseppe
AU - Meijerink, Jules P.
AU - Cordon-Cardo, Carlos
AU - Califano, Andrea
AU - Ferrando, Adolfo A.
N1 - Funding Information:
This work was supported by the National Institutes of Health (grants R01CA129382 to A.A.F., U24 CA114737 to E.P., RC2 CA148308 to A.C. and A.F., and U54CA121852 to A.C.), the Stand Up To Cancer Innovative Research Award (to A.A.F.), the Chemotherapy Foundation (to A.A.F.), the Leukemia & Lymphoma Society Scholar Award (to A.A.F.), a Leukemia & Lymphoma Society SCOR Grant (to A.A.F.), and the ECOG Leukemia Tissue Bank. We are grateful to A. Kung for the FUW-luc vector, J. Aster for the MigR1- NOTCH1 L1601PΔP vector, P.P. Pandolfi for the Pten f conditional knockout mouse, T. Ludwig for the ROSA26 Cre-ERT2/+ mouse, S. Minuzzo for generation of T-ALL xenografts, L. Xu for help in animal procedures, M.A. Gawinowicz from the Proteomics Share Resource at the Herbert Irving Comprehensive Cancer Center at Columbia University for assistance in mass spectrometry analysis, and R. Baer for helpful discussions and revision of the manuscript.
PY - 2013/12/9
Y1 - 2013/12/9
N2 - Glucocorticoid resistance is a major driver of therapeutic failure in Tcell 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 invitro and invivo.
AB - Glucocorticoid resistance is a major driver of therapeutic failure in Tcell 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 invitro and invivo.
UR - https://www.scopus.com/pages/publications/84891913160
UR - https://www.scopus.com/pages/publications/84891913160#tab=citedBy
U2 - 10.1016/j.ccr.2013.10.022
DO - 10.1016/j.ccr.2013.10.022
M3 - Article
C2 - 24291004
AN - SCOPUS:84891913160
SN - 1535-6108
VL - 24
SP - 766
EP - 776
JO - Cancer Cell
JF - Cancer Cell
IS - 6
ER -