Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia
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 i...
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| Veröffentlicht in: | Cancer cell 2013-12, Vol.24 (6), p.766-776 |
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| creator | Piovan, Erich Yu, Jiyang Tosello, Valeria Herranz, Daniel Ambesi-Impiombato, Alberto Da Silva, Ana Carolina Sanchez-Martin, Marta Perez-Garcia, Arianne Rigo, Isaura Castillo, Mireia Indraccolo, Stefano Cross, Justin R. de Stanchina, Elisa Paietta, Elisabeth Racevskis, Janis Rowe, Jacob M. Tallman, Martin S. Basso, Giuseppe Meijerink, Jules P. Cordon-Cardo, Carlos Califano, Andrea Ferrando, Adolfo A. |
| description | 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.
•AKT1 directly phosphorylates the NR3C1 glucocorticoid receptor protein•AKT-mediated S134 phosphorylation blocks nuclear translocation of NR3C1•PTEN loss and AKT1 activation induce glucocorticoid resistance in T-ALL•Pharmacologic inhibition of AKT1 reverses glucocorticoid resistance in T-ALL |
| doi_str_mv | 10.1016/j.ccr.2013.10.022 |
| format | Article |
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•AKT1 directly phosphorylates the NR3C1 glucocorticoid receptor protein•AKT-mediated S134 phosphorylation blocks nuclear translocation of NR3C1•PTEN loss and AKT1 activation induce glucocorticoid resistance in T-ALL•Pharmacologic inhibition of AKT1 reverses glucocorticoid resistance in T-ALL</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2013.10.022</identifier><identifier>PMID: 24291004</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Active Transport, Cell Nucleus ; Animals ; Dexamethasone - therapeutic use ; Drug Resistance, Neoplasm ; Heterocyclic Compounds, 3-Ring - pharmacology ; Humans ; Mice ; Phosphorylation ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - physiology ; PTEN Phosphohydrolase - physiology ; Receptors, Glucocorticoid - metabolism</subject><ispartof>Cancer cell, 2013-12, Vol.24 (6), p.766-776</ispartof><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><rights>2013 Elsevier Inc. All rights reserved. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-1a4d553864a2841d028cae65b17e65bbedad8a1c3fec91efc3b5fb6659e09f773</citedby><cites>FETCH-LOGICAL-c517t-1a4d553864a2841d028cae65b17e65bbedad8a1c3fec91efc3b5fb6659e09f773</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610813004637$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24291004$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Piovan, Erich</creatorcontrib><creatorcontrib>Yu, Jiyang</creatorcontrib><creatorcontrib>Tosello, Valeria</creatorcontrib><creatorcontrib>Herranz, Daniel</creatorcontrib><creatorcontrib>Ambesi-Impiombato, Alberto</creatorcontrib><creatorcontrib>Da Silva, Ana Carolina</creatorcontrib><creatorcontrib>Sanchez-Martin, Marta</creatorcontrib><creatorcontrib>Perez-Garcia, Arianne</creatorcontrib><creatorcontrib>Rigo, Isaura</creatorcontrib><creatorcontrib>Castillo, Mireia</creatorcontrib><creatorcontrib>Indraccolo, Stefano</creatorcontrib><creatorcontrib>Cross, Justin R.</creatorcontrib><creatorcontrib>de Stanchina, Elisa</creatorcontrib><creatorcontrib>Paietta, Elisabeth</creatorcontrib><creatorcontrib>Racevskis, Janis</creatorcontrib><creatorcontrib>Rowe, Jacob M.</creatorcontrib><creatorcontrib>Tallman, Martin S.</creatorcontrib><creatorcontrib>Basso, Giuseppe</creatorcontrib><creatorcontrib>Meijerink, Jules P.</creatorcontrib><creatorcontrib>Cordon-Cardo, Carlos</creatorcontrib><creatorcontrib>Califano, Andrea</creatorcontrib><creatorcontrib>Ferrando, Adolfo A.</creatorcontrib><title>Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>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.
•AKT1 directly phosphorylates the NR3C1 glucocorticoid receptor protein•AKT-mediated S134 phosphorylation blocks nuclear translocation of NR3C1•PTEN loss and AKT1 activation induce glucocorticoid resistance in T-ALL•Pharmacologic inhibition of AKT1 reverses glucocorticoid resistance in T-ALL</description><subject>Active Transport, Cell Nucleus</subject><subject>Animals</subject><subject>Dexamethasone - therapeutic use</subject><subject>Drug Resistance, Neoplasm</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacology</subject><subject>Humans</subject><subject>Mice</subject><subject>Phosphorylation</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - physiology</subject><subject>PTEN Phosphohydrolase - physiology</subject><subject>Receptors, Glucocorticoid - metabolism</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0Eoh_wA7ggH7lk8SSx4wgJadXSUrFSJdReazmTCesliRc7WWn_PV62VHDpxV_zvq9H8zD2DsQCBKiPmwViWOQCinRfiDx_wU5BVzorlFYv01kWMlMg9Ak7i3Ejkgeq-jU7ycu8BiHKU_Zw6QLhxL_TjkK0Pfcdv-5n9OjD5NC7NpWii5MdkXiz58tvd_xmXLvGTc6P3I18ifNEfLUftmvf9DYmG1_R_JMGZ9-wV53tI7193M_Z_dWXu4uv2er2-uZiucpQQjVlYMtWykKr0ua6hFbkGi0p2UB1WBtqbastYNER1kAdFo3sGqVkTaLuqqo4Z5-Pudu5GahFGqdge7MNbrBhb7x15v_K6Nbmh9-ZIo1LSZ0CPjwGBP9rpjiZwUWkvrcj-TkaKFWtSpF6TFI4SjH4GAN1T9-AMAcuZmMSF3PgcnhKXJLn_b_9PTn-gkiCT0cBpSntHAUT0VGaefuHj2m9eyb-NzqcoCo</recordid><startdate>20131209</startdate><enddate>20131209</enddate><creator>Piovan, Erich</creator><creator>Yu, Jiyang</creator><creator>Tosello, Valeria</creator><creator>Herranz, Daniel</creator><creator>Ambesi-Impiombato, Alberto</creator><creator>Da Silva, Ana Carolina</creator><creator>Sanchez-Martin, Marta</creator><creator>Perez-Garcia, Arianne</creator><creator>Rigo, Isaura</creator><creator>Castillo, Mireia</creator><creator>Indraccolo, Stefano</creator><creator>Cross, Justin R.</creator><creator>de Stanchina, Elisa</creator><creator>Paietta, Elisabeth</creator><creator>Racevskis, Janis</creator><creator>Rowe, Jacob M.</creator><creator>Tallman, Martin S.</creator><creator>Basso, Giuseppe</creator><creator>Meijerink, Jules P.</creator><creator>Cordon-Cardo, Carlos</creator><creator>Califano, Andrea</creator><creator>Ferrando, Adolfo A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20131209</creationdate><title>Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia</title><author>Piovan, Erich ; 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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.
•AKT1 directly phosphorylates the NR3C1 glucocorticoid receptor protein•AKT-mediated S134 phosphorylation blocks nuclear translocation of NR3C1•PTEN loss and AKT1 activation induce glucocorticoid resistance in T-ALL•Pharmacologic inhibition of AKT1 reverses glucocorticoid resistance in T-ALL</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24291004</pmid><doi>10.1016/j.ccr.2013.10.022</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Active Transport, Cell Nucleus Animals Dexamethasone - therapeutic use Drug Resistance, Neoplasm Heterocyclic Compounds, 3-Ring - pharmacology Humans Mice Phosphorylation Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - physiology PTEN Phosphohydrolase - physiology Receptors, Glucocorticoid - metabolism |
| title | Direct Reversal of Glucocorticoid Resistance by AKT Inhibition in Acute Lymphoblastic Leukemia |
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