| S6K1 determines the metabolic requirements for BCR-ABL survival. | |
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MedLine Citation:
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PMID: 22391570 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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In chronic myelogenous leukemia, the constitutive activation of the BCR-ABL kinase transforms cells to an addicted state that requires glucose metabolism for survival. We investigated S6K1, a protein kinase that drives glycolysis in leukemia cells, as a target for counteracting glucose-dependent survival induced by BCR-ABL. BCR-ABL potently activated S6K1-dependent signaling and glycolysis. Although S6K1 knockdown or rapamycin treatment suppressed glycolysis in BCR-ABL-transformed cells, these treatments did not induce cell death. Instead, loss of S6K1 triggered compensatory activation of fatty-acid oxidation, a metabolic program that can support glucose-independent cell survival. Fatty-acid oxidation in response to S6K1 inactivation required the expression of the fatty-acid transporter carnitine palmitoyl transferase 1c, which was recently linked to rapamycin resistance in cancer. Finally, addition of an inhibitor of fatty-acid oxidation significantly enhanced cytotoxicity in response to S6K1 inactivation. These data indicate that S6K1 dictates the metabolic requirements mediating BCR-ABL survival and provide a rationale for combining targeted inhibitors of signal transduction, with strategies to interrupt oncogene-induced metabolism.Oncogene advance online publication, 5 March 2012; doi:10.1038/onc.2012.70. |
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Authors:
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J F Barger; C A Gallo; P Tandon; H Liu; A Sullivan; H L Grimes; D R Plas |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-3-05 |
Journal Detail:
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Title: Oncogene Volume: - ISSN: 1476-5594 ISO Abbreviation: - Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-3-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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