Determining mechanistic details about how drugs kill cancer cells is critical for predicting which cancers will respond to given therapeutic regimens and for identifying effective combinations of drugs that more potently kill cancer cells while sparing normal cells. The BCL2 family of proteins and bioactive sphingolipids are intricately linked during apoptotic cell death. In fact, many chemotherapeutic drugs are known to cause accumulation of the pro-apoptotic sphingolipid ceramide; however, the mechanism by which this occurs is not completely understood. In the present study we demonstrate that direct inhibition of anti-apoptotic BCL2 proteins with ABT-263 is sufficient to induce C16-ceramide synthesis in multiple cell lines, including human leukaemia and myeloma cells. ABT-263 activates CerS (ceramide synthase) activity only in cells expressing BAK or in cells capable of activating BAK. Importantly, recombinant BAK is sufficient to increase in vitro CerS activity in microsomes purified from Bak-KO (knockout) cells and activated BAK more potently activates CerS than inactive BAK. Likewise, ABT-263 addition to wild-type, but not Bak-deficient, microsomes increases CerS in vitro activity. Furthermore, we present a feed-forward model by which BAK activation of CerS by chemotherapeutic drugs leads to elevated ceramide levels that result in synergistic channel formation by ceramide (or one of its metabolites) and BAX/BAK.
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Research Article|
April 25 2013
BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins
Levi J. Beverly;
Levi J. Beverly
1
*Division of Hematology and Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
1Correspondence may be addressed to either of these authors (email levi.beverly@louisville.edu or siskind@musc.edu).
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Lauren A. Howell;
Lauren A. Howell
†Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy at the Medical School of South Carolina, Charleston, SC 29425, U.S.A.
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Maria Hernandez-Corbacho;
Maria Hernandez-Corbacho
‡Department of Medicine, Stony Brook University, Stony Brook, NY 11794, U.S.A.
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Lavona Casson;
Lavona Casson
*Division of Hematology and Oncology, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, U.S.A.
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Jerry E. Chipuk;
Jerry E. Chipuk
§Mount Sinai School of Medicine, Department of Oncological Sciences, New York, NY 10029, U.S.A.
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Leah J. Siskind
Leah J. Siskind
1
†Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy at the Medical School of South Carolina, Charleston, SC 29425, U.S.A.
∥Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, U.S.A.
1Correspondence may be addressed to either of these authors (email levi.beverly@louisville.edu or siskind@musc.edu).
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Publisher: Portland Press Ltd
Received:
January 25 2013
Revision Received:
February 12 2013
Accepted:
March 12 2013
Accepted Manuscript online:
March 12 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 452 (1): 111–119.
Article history
Received:
January 25 2013
Revision Received:
February 12 2013
Accepted:
March 12 2013
Accepted Manuscript online:
March 12 2013
Citation
Levi J. Beverly, Lauren A. Howell, Maria Hernandez-Corbacho, Lavona Casson, Jerry E. Chipuk, Leah J. Siskind; BAK activation is necessary and sufficient to drive ceramide synthase-dependent ceramide accumulation following inhibition of BCL2-like proteins. Biochem J 15 May 2013; 452 (1): 111–119. doi: https://doi.org/10.1042/BJ20130147
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