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

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

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)83208-83222
Number of pages15
JournalOncotarget
Volume7
Issue number50
DOIs
StatePublished - Jan 1 2016

All Science Journal Classification (ASJC) codes

  • Oncology

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    Tan, S. F., Liu, X., Fox, T. E., Barth, B. M., Sharma, A., Turner, S. D., Awwad, A., Dewey, A., Doi, K., Spitzer, B., Shah, M. V., Morad, S. A. F., Desai, D., Amin, S., Zhu, J., Liao, J., Yun, J., Kester, M., Claxton, D. F., ... Loughran, T. P. (2016). Acid ceramidase is upregulated in AML and represents a novel therapeutic target. Oncotarget, 7(50), 83208-83222. https://doi.org/10.18632/oncotarget.13079