Acid ceramidase is upregulated in AML and represents a novel therapeutic target
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Su-Fern Tan1, Xin Liu2, Todd E. Fox3, Brian M. Barth4, Arati Sharma2, Stephen D. Turner5, Andy Awwad2, Alden Dewey2, Kenichiro Doi6, Barbara Spitzer7, Mithun Vinod Shah8, Samy A.F. Morad9,10, Dhimant Desai11, Shantu Amin11, Junjia Zhu2, Jason Liao2, Jong Yun2,11, Mark Kester3, David F. Claxton2, Hong-Gang Wang2,12, Myles C. Cabot9, Edward H. Schuchman13, Ross L. Levine7, David J. Feith1,14, Thomas P. Loughran Jr1,14
1Department of Medicine, University of Virginia, Charlottesville, VA, USA
2Penn State Hershey Cancer Institute, Hershey, PA, USA
3Department of Pharmacology, University of Virginia, Charlottesville, VA, USA
4Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH, USA
5Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA
6Department of Pathology, Osaka City University Medical School, Osaka, Japan
7Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
8Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
9Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC, USA
10Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
11Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
12Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA
13Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, USA
14University of Virginia Cancer Center, Charlottesville, VA, USA
Thomas P. Loughran Jr, email: [email protected]
Keywords: acid ceramidase, myeloid cell leukemia sequence 1 protein, ceramide, sphingosine 1-phosphate, leukemia
Received: May 20, 2016 Accepted: October 13, 2016 Published: November 4, 2016
There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML.
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