Acid ceramidase is upregulated in AML and represents a novel therapeutic target
| Autor: | Jong K. Yun, Dhimant Desai, Brian M. Barth, Thomas P. Loughran, Andy Awwad, Mark Kester, Hong Gang Wang, Stephen D. Turner, Xin Liu, Samy A.F. Morad, Edward H. Schuchman, Kenichiro Doi, David J. Feith, Arati Sharma, Ross L. Levine, Junjia Zhu, Todd E. Fox, Su Fern Tan, Alden Dewey, Myles C. Cabot, David F. Claxton, Barbara Spitzer, Mithun Vinod Shah, Shantu Amin, Jason Liao |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Gerontology Oncology Time Factors Acid Ceramidase Apoptosis 0302 clinical medicine Sphingosine hemic and lymphatic diseases Tumor Cells Cultured Molecular Targeted Therapy Enzyme Inhibitors leukemia Myeloid leukemia humanities 3. Good health Up-Regulation Gene Expression Regulation Neoplastic Leukemia Leukemia Myeloid Acute myeloid cell leukemia sequence 1 protein 030220 oncology & carcinogenesis Female RNA Interference Signal Transduction Research Paper medicine.medical_specialty Cell Survival Ceramide breakdown Antineoplastic Agents HL-60 Cells Ceramides Transfection Gene Expression Regulation Enzymologic Unmet needs 03 medical and health sciences Internal medicine medicine Overall survival Biomarkers Tumor Animals Humans ceramide sphingosine 1-phosphate Dose-Response Relationship Drug business.industry Cancer medicine.disease Xenograft Model Antitumor Assays Transplantation Mice Inbred C57BL 030104 developmental biology Lysophospholipids business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Su-Fern Tan 1 , Xin Liu 2 , Todd E. Fox 3 , Brian M. Barth 4 , Arati Sharma 2 , Stephen D. Turner 5 , Andy Awwad 2 , Alden Dewey 2 , Kenichiro Doi 6 , Barbara Spitzer 7 , Mithun Vinod Shah 8 , Samy A.F. Morad 9, 10 , Dhimant Desai 11 , Shantu Amin 11 , Junjia Zhu 2 , Jason Liao 2 , Jong Yun 2, 11 , Mark Kester 3 , David F. Claxton 2 , Hong-Gang Wang 2, 12 , Myles C. Cabot 9 , Edward H. Schuchman 13 , Ross L. Levine 7 , David J. Feith 1, 14 , Thomas P. Loughran, Jr 1, 14 1 Department of Medicine, University of Virginia, Charlottesville, VA, USA 2 Penn State Hershey Cancer Institute, Hershey, PA, USA 3 Department of Pharmacology, University of Virginia, Charlottesville, VA, USA 4 Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH, USA 5 Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA 6 Department of Pathology, Osaka City University Medical School, Osaka, Japan 7 Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA 8 Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC, USA 10 Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt 11 Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA 12 Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA 13 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, New York, USA 14 University of Virginia Cancer Center, Charlottesville, VA, USA Correspondence to: Thomas P. Loughran, Jr, email: tploughran@virginia.edu 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 ABSTRACT 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. |
| Databáze: | OpenAIRE |
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