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S6K1 determines the metabolic requirements for BCR-ABL survival

Oncogene volume 32, pages 453–461 (2013)Cite this article

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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.

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Acknowledgements

We thank Drs George Thomas and Sara Kozma for their advice and access to S6K1 knockout mice. We thank Dr Shane Horman, Jim Phelan and Meghan Brundage for their help with CML models in mice, and Drs Czyzyk-Krzeska and Godar for critique of the manuscript. JFB was supported by an IGERT fellowship #0333377. This work was supported by NIH Grant CA133164, the American Cancer Society RSG-08-293-01-CCG and the University of Cincinnati's Millennium Scholars program.

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Authors and Affiliations

  1. Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH, USA

    J F Barger, C A Gallo, P Tandon, H Liu, A Sullivan & D R Plas

  2. Divisions of Immunobiology and Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, OH, USA

    H L Grimes

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  1. J F Barger
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  2. C A Gallo
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  3. P Tandon
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  4. H Liu
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Correspondence to D R Plas.

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Barger, J., Gallo, C., Tandon, P. et al. S6K1 determines the metabolic requirements for BCR-ABL survival. Oncogene 32, 453–461 (2013). https://doi.org/10.1038/onc.2012.70

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