Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carnitine O-Palmitoyltransferase / genetics
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Carnitine O-Palmitoyltransferase / metabolism
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Cell Death / drug effects
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Cell Death / genetics
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / physiology
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Fatty Acid Transport Proteins / genetics
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Fatty Acid Transport Proteins / metabolism
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Fatty Acids / genetics
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Fatty Acids / metabolism
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism*
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Glucose / genetics
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Glucose / metabolism
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Glycolysis / drug effects
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Glycolysis / genetics
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
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Mice
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Mice, Inbred C57BL
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Oxidation-Reduction / drug effects
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Sirolimus / pharmacology
Substances
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Fatty Acid Transport Proteins
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Fatty Acids
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Carnitine O-Palmitoyltransferase
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Fusion Proteins, bcr-abl
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Ribosomal Protein S6 Kinases, 70-kDa
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ribosomal protein S6 kinase, 70kD, polypeptide 1
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Glucose
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Sirolimus