Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia Journal Article
| Authors: | Piovan, E.; Yu, J.; Tosello, V.; Herranz, D.; Ambesi-Impiombato, A.; DaSilva, A.; Sanchez-Martin, M.; Perez-Garcia, A.; Rigo, I.; Castillo, M.; Indraccolo, S.; Cross, J.; Destanchina, E.; Paietta, E.; Racevskis, J.; Rowe, J.; Tallman, M.; Basso, G.; Meijerink, J.; Cordon-Cardo, C.; Califano, A.; Ferrando, A. |
| Article Title: | Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia |
| 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. © 2013 Elsevier Inc. |
| Journal Title: | Cancer Cell |
| Volume: | 24 |
| Issue: | 6 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2013-12-09 |
| Start Page: | 766 |
| End Page: | 776 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2013.10.022 |
| PROVIDER: | scopus |
| PMCID: | PMC3878658 |
| PUBMED: | 24291004 |
| DOI/URL: | |
| Notes: | Export Date: 3 February 2014 -- CODEN: CCAEC -- Source: Scopus |
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