Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 766-776 |
| Number of pages | 11 |
| Journal | Cancer Cell |
| Volume | 24 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Dec 9 2013 |
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ASJC Scopus subject areas
- Cancer Research
- Cell Biology
- Oncology
Cite this
Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia. / Piovan, Erich; Yu, Jiyang; Tosello, Valeria; Herranz, Daniel; Ambesi-Impiombato, Alberto; DaSilva, AnaCarolina; Sanchez-Martin, Marta; Perez-Garcia, Arianne; Rigo, Isaura; Castillo, Mireia; Indraccolo, Stefano; Cross, JustinR; deStanchina, Elisa; Paietta, Elisabeth; Racevskis, Janis; Rowe, JacobM; Tallman, MartinS; Basso, Giuseppe; Meijerink, JulesP; Cordon-Cardo, Carlos; Califano, Andrea; Ferrando, AdolfoA.
In: Cancer Cell, Vol. 24, No. 6, 09.12.2013, p. 766-776.Research output: Contribution to journal › Article
}
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, AnaCarolina
AU - Sanchez-Martin, Marta
AU - Perez-Garcia, Arianne
AU - Rigo, Isaura
AU - Castillo, Mireia
AU - Indraccolo, Stefano
AU - Cross, JustinR
AU - deStanchina, Elisa
AU - Paietta, Elisabeth
AU - Racevskis, Janis
AU - Rowe, JacobM
AU - Tallman, MartinS
AU - Basso, Giuseppe
AU - Meijerink, JulesP
AU - Cordon-Cardo, Carlos
AU - Califano, Andrea
AU - Ferrando, AdolfoA
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 - http://www.scopus.com/inward/record.url?scp=84891913160&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891913160&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2013.10.022
DO - 10.1016/j.ccr.2013.10.022
M3 - Article
C2 - 24291004
AN - SCOPUS:84891913160
VL - 24
SP - 766
EP - 776
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -