Acid ceramidase is upregulated in AML and represents a novel therapeutic target.
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.
Department of Medicine, University of Virginia, Charlottesville, VA, USA.
Su-Fern
SF
Tan
Penn State Hershey Cancer Institute, Hershey, PA, USA.
Xin
X
Liu
Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
Todd E
TE
Fox
Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH, USA.
Brian M
BM
Barth
Penn State Hershey Cancer Institute, Hershey, PA, USA.
Arati
A
Sharma
Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
Stephen D
SD
Turner
Penn State Hershey Cancer Institute, Hershey, PA, USA.
Andy
A
Awwad
Penn State Hershey Cancer Institute, Hershey, PA, USA.
Alden
A
Dewey
Department of Pathology, Osaka City University Medical School, Osaka, Japan.
Kenichiro
K
Doi
Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Barbara
B
Spitzer
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mithun Vinod
MV
Shah
Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC, USA.|Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
Samy A F
SA
Morad
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Dhimant
D
Desai
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Shantu
S
Amin
Penn State Hershey Cancer Institute, Hershey, PA, USA.
Junjia
J
Zhu
Penn State Hershey Cancer Institute, Hershey, PA, USA.
Jason
J
Liao
Penn State Hershey Cancer Institute, Hershey, PA, USA.|Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Jong
J
Yun
Department of Pharmacology, University of Virginia, Charlottesville, VA, USA.
Mark
M
Kester
Penn State Hershey Cancer Institute, Hershey, PA, USA.
David F
DF
Claxton
Penn State Hershey Cancer Institute, Hershey, PA, USA.|Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Hong-Gang
HG
Wang
Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC, USA.
Myles C
MC
Cabot
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, USA.
Edward H
EH
Schuchman
Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ross L
RL
Levine
Department of Medicine, University of Virginia, Charlottesville, VA, USA.|University of Virginia Cancer Center, Charlottesville, VA, USA.
David J
DJ
Feith
Department of Medicine, University of Virginia, Charlottesville, VA, USA.|University of Virginia Cancer Center, Charlottesville, VA, USA.
Thomas P
TP
Loughran
D055573:Acid Ceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002518:Ceramides; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C060506:sphingosine 1-phosphate; C526693:ASAH1 protein, human; D055573:Acid Ceramidase; D013110:Sphingosine
acid ceramidase; ceramide; leukemia; myeloid cell leukemia sequence 1 protein; sphingosine 1-phosphate