Cancer cells are hypersensitive to nutrient limitation because oncogenes constitutively drive glycolytic and TCA (tricarboxylic acid) cycle intermediates into biosynthetic pathways. As the anaplerotic reactions that replace these intermediates are fueled by imported nutrients, the cancer cell's ability to generate ATP becomes compromised under nutrient-limiting conditions. In addition, most cancer cells have defects in autophagy, the catabolic process that provides nutrients from internal sources when external nutrients are unavailable. Normal cells, in contrast, can adapt to the nutrient stress that kills cancer cells by becoming quiescent and catabolic. In the present study we show that FTY720, a water-soluble sphingolipid drug that is effective in many animal cancer models, selectively starves cancer cells to death by down-regulating nutrient transporter proteins. Consistent with a bioenergetic mechanism of action, FTY720 induced homoeostatic autophagy. Cells were protected from FTY720 by cell-permeant nutrients or by reducing nutrient demand, but blocking apoptosis was ineffective. Importantly, AAL-149, a FTY720 analogue that lacks FTY720's dose-limiting toxicity, also triggered transporter loss and killed patient-derived leukaemias while sparing cells isolated from normal donors. As they target the metabolic profile of cancer cells rather than specific oncogenic mutations, FTY720 analogues such as AAL-149 should be effective against many different tumour types, particularly in combination with drugs that inhibit autophagy.
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October 2011
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Research Article|
September 28 2011
Sphingolipid-based drugs selectively kill cancer cells by down-regulating nutrient transporter proteins
Kimberly Romero Rosales;
Kimberly Romero Rosales
*Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, U.S.A.
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Gurpreet Singh;
Gurpreet Singh
*Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, U.S.A.
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Kevin Wu;
Kevin Wu
*Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, U.S.A.
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Jie Chen;
Jie Chen
†Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, U.S.A.
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Matthew R. Janes;
Matthew R. Janes
‡Department of Molecular Biology and Biochemistry and Institute for Immunology, University of California, Irvine, CA 92697, U.S.A.
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Michael B. Lilly;
Michael B. Lilly
§Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA 92697, U.S.A.
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Eigen R. Peralta;
Eigen R. Peralta
*Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, U.S.A.
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Leah J. Siskind;
Leah J. Siskind
∥Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, U.S.A.
¶Medical University of South Carolina, Department of Medicine, Division of General Internal Medicine/Geriatrics, Charleston, SC 29425, U.S.A.
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Michael J. Bennett;
Michael J. Bennett
†Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, U.S.A.
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David A. Fruman;
David A. Fruman
‡Department of Molecular Biology and Biochemistry and Institute for Immunology, University of California, Irvine, CA 92697, U.S.A.
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Aimee L. Edinger
Aimee L. Edinger
1
*Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, U.S.A.
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
May 11 2011
Revision Received:
July 01 2011
Accepted:
July 18 2011
Accepted Manuscript online:
July 18 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 439 (2): 299–311.
Article history
Received:
May 11 2011
Revision Received:
July 01 2011
Accepted:
July 18 2011
Accepted Manuscript online:
July 18 2011
Citation
Kimberly Romero Rosales, Gurpreet Singh, Kevin Wu, Jie Chen, Matthew R. Janes, Michael B. Lilly, Eigen R. Peralta, Leah J. Siskind, Michael J. Bennett, David A. Fruman, Aimee L. Edinger; Sphingolipid-based drugs selectively kill cancer cells by down-regulating nutrient transporter proteins. Biochem J 15 October 2011; 439 (2): 299–311. doi: https://doi.org/10.1042/BJ20110853
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