Journal
ONCOGENE
Volume 32, Issue 4, Pages 453-461Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.70
Keywords
S6K1; glycolysis; fatty-acid oxidation; rapamycin; leukemia; Cpt1c
Funding
- IGERT [0333377]
- NIH [CA133164]
- American Cancer Society [RSG-08-293-01-CCG]
- University of Cincinnati
- Division Of Graduate Education
- Direct For Education and Human Resources [0333377] Funding Source: National Science Foundation
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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 (2013) 32, 453-461; doi:10.1038/onc.2012.70; published online 5 March 2012
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