Acid ceramidase is upregulated in AML and represents a novel therapeutic target.

Academic Article

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.
  • Authors

  • Tan, Su-Fern
  • Liu, Xin
  • Fox, Todd E
  • Barth, Brian
  • Sharma, Arati
  • Turner, Stephen D
  • Awwad, Andy
  • Dewey, Alden
  • Doi, Kenichiro
  • Spitzer, Barbara
  • Shah, Mithun Vinod
  • Morad, Samy AF
  • Desai, Dhimant
  • Amin, Shantu
  • Zhu, Junjia
  • Liao, Jason
  • Yun, Jong
  • Kester, Mark
  • Claxton, David F
  • Wang, Hong-Gang
  • Cabot, Myles C
  • Schuchman, Edward H
  • Levine, Ross L
  • Feith, David J
  • Loughran, Thomas P
  • Status

    Publication Date

  • December 13, 2016
  • Published In

  • Oncotarget  Journal
  • Keywords

  • Acid Ceramidase
  • Animals
  • Antineoplastic Agents
  • Apoptosis
  • Biomarkers, Tumor
  • Cell Survival
  • Ceramides
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid, Acute
  • Lysophospholipids
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Myeloid Cell Leukemia Sequence 1 Protein
  • RNA Interference
  • Signal Transduction
  • Sphingosine
  • Time Factors
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation
  • Xenograft Model Antitumor Assays
  • acid ceramidase
  • ceramide
  • leukemia
  • myeloid cell leukemia sequence 1 protein
  • sphingosine 1-phosphate
  • Digital Object Identifier (doi)

    Start Page

  • 83208
  • End Page

  • 83222
  • Volume

  • 7
  • Issue

  • 50