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Cancer Genes and Networks

Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia

Jennifer M. Pearson, Su-Fern Tan, Arati Sharma, Charyguly Annageldiyev, Todd E. Fox, Jose Luis Abad, Gemma Fabrias, Dhimant Desai, Shantu Amin, Hong-Gang Wang, Myles C. Cabot, David F. Claxton, Mark Kester, David J. Feith and Thomas P. Loughran
Jennifer M. Pearson
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
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Su-Fern Tan
2Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia.
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Arati Sharma
3Penn State Cancer Institute, Hershey, Pennsylvania.
4Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
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Charyguly Annageldiyev
3Penn State Cancer Institute, Hershey, Pennsylvania.
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Todd E. Fox
5Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
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Jose Luis Abad
6Department of Biological Chemistry, Networking Biomedical Research Centre on Liver and Digestive Diseases (CIBER-EHD), Institute for Advanced Chemistry of Catalonia, Spanish National Research Council (IQAC-CSIC), Barcelona, Spain.
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Gemma Fabrias
6Department of Biological Chemistry, Networking Biomedical Research Centre on Liver and Digestive Diseases (CIBER-EHD), Institute for Advanced Chemistry of Catalonia, Spanish National Research Council (IQAC-CSIC), Barcelona, Spain.
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Dhimant Desai
4Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
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Shantu Amin
4Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
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Hong-Gang Wang
3Penn State Cancer Institute, Hershey, Pennsylvania.
7Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
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Myles C. Cabot
8Department of Biochemistry and Molecular Biology, East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, North Carolina.
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David F. Claxton
3Penn State Cancer Institute, Hershey, Pennsylvania.
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Mark Kester
4Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
9University of Virginia Cancer Center, Charlottesville, Virginia.
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David J. Feith
2Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia.
9University of Virginia Cancer Center, Charlottesville, Virginia.
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Thomas P. Loughran
2Department of Medicine, Division of Hematology & Oncology, University of Virginia, Charlottesville, Virginia.
9University of Virginia Cancer Center, Charlottesville, Virginia.
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  • For correspondence: TL7CS@virginia.edu
DOI: 10.1158/1541-7786.MCR-19-0619 Published March 2020
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Abstract

Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. The 5-year survival rate is approximately 25%, and recent therapeutic developments have yielded little survival benefit. Therefore, there is an urgent need to identify novel therapeutic targets. We previously demonstrated that acid ceramidase (ASAH1, referred to as AC) is upregulated in AML and high AC activity correlates with poor patient survival. Here, we characterized a novel AC inhibitor, SACLAC, that significantly reduced the viability of AML cells with an EC50 of approximately 3 μmol/L across 30 human AML cell lines. Treatment of AML cell lines with SACLAC effectively blocked AC activity and induced a decrease in sphingosine 1-phosphate and a 2.5-fold increase in total ceramide levels. Mechanistically, we showed that SACLAC treatment led to reduced levels of splicing factor SF3B1 and alternative MCL-1 mRNA splicing in multiple human AML cell lines. This increased proapoptotic MCL-1S levels and contributed to SACLAC-induced apoptosis in AML cells. The apoptotic effects of SACLAC were attenuated by SF3B1 or MCL-1 overexpression and by selective knockdown of MCL-1S. Furthermore, AC knockdown and exogenous C16-ceramide supplementation induced similar changes in SF3B1 level and MCL-1S/L ratio. Finally, we demonstrated that SACLAC treatment leads to a 37% to 75% reduction in leukemic burden in two human AML xenograft mouse models.

Implications: These data further emphasize AC as a therapeutic target in AML and define SACLAC as a potent inhibitor to be further optimized for future clinical development.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:352–63

  • Received June 11, 2019.
  • Revision received August 30, 2019.
  • Accepted November 15, 2019.
  • Published first November 19, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 18 (3)
March 2020
Volume 18, Issue 3
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Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia
Jennifer M. Pearson, Su-Fern Tan, Arati Sharma, Charyguly Annageldiyev, Todd E. Fox, Jose Luis Abad, Gemma Fabrias, Dhimant Desai, Shantu Amin, Hong-Gang Wang, Myles C. Cabot, David F. Claxton, Mark Kester, David J. Feith and Thomas P. Loughran
Mol Cancer Res March 1 2020 (18) (3) 352-363; DOI: 10.1158/1541-7786.MCR-19-0619

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Ceramide Analogue SACLAC Modulates Sphingolipid Levels and MCL-1 Splicing to Induce Apoptosis in Acute Myeloid Leukemia
Jennifer M. Pearson, Su-Fern Tan, Arati Sharma, Charyguly Annageldiyev, Todd E. Fox, Jose Luis Abad, Gemma Fabrias, Dhimant Desai, Shantu Amin, Hong-Gang Wang, Myles C. Cabot, David F. Claxton, Mark Kester, David J. Feith and Thomas P. Loughran
Mol Cancer Res March 1 2020 (18) (3) 352-363; DOI: 10.1158/1541-7786.MCR-19-0619
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