Acid ceramidase is upregulated in AML and represents a novel therapeutic target
Author
Tan, Su-Fern; Liu, Xin; Fox, Todd E.; Barth, Brian M.; Sharma, Arati; Turner, Stephen D.; Awwad, Andy; Dewey, Alden; Doi, Kenichiro; Spitzer, Barbara; Shah, Mithun Vinod; Morad, Samy A.F.; 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. Jr.
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.
Date
2016-12-13
Citation:
APA:
Tan, Su-Fern, & Liu, Xin, & Fox, Todd E., & Barth, Brian M., & Sharma, Arati, & Turner, Stephen D., & Awwad, Andy, & Dewey, Alden, & Doi, Kenichiro, & Spitzer, Barbara, & Shah, Mithun Vinod, & Morad, Samy A.F., & 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. Jr.. (December 2016).
Acid ceramidase is upregulated in AML and represents a novel therapeutic target.
,
(),
-
. Retrieved from
http://hdl.handle.net/10342/8448
MLA:
Tan, Su-Fern, and Liu, Xin, and Fox, Todd E., and Barth, Brian M., and Sharma, Arati, and Turner, Stephen D., and Awwad, Andy, and Dewey, Alden, and Doi, Kenichiro, and Spitzer, Barbara, and Shah, Mithun Vinod, and Morad, Samy A.F., and Desai, Dhimant, and Amin, Shantu, and Zhu, Junjia, and Liao, Jason, and Yun, Jong, and Kester, Mark, and Claxton, David F., and Wang, Hong-Gang, and Cabot, Myles C., and Schuchman, Edward H., and Levine, Ross L., and Feith, David J., and Loughran, Thomas P. Jr..
"Acid ceramidase is upregulated in AML and represents a novel therapeutic target". .
. (),
December 2016.
September 21, 2023.
http://hdl.handle.net/10342/8448.
Chicago:
Tan, Su-Fern and Liu, Xin and Fox, Todd E. and Barth, Brian M. and Sharma, Arati and Turner, Stephen D. and Awwad, Andy and Dewey, Alden and Doi, Kenichiro and Spitzer, Barbara and Shah, Mithun Vinod and Morad, Samy A.F. and Desai, Dhimant and Amin, Shantu and Zhu, Junjia and Liao, Jason and Yun, Jong and Kester, Mark and Claxton, David F. and Wang, Hong-Gang and Cabot, Myles C. and Schuchman, Edward H. and Levine, Ross L. and Feith, David J. and Loughran, Thomas P. Jr.,
"Acid ceramidase is upregulated in AML and represents a novel therapeutic target," , no.
(December 2016),
http://hdl.handle.net/10342/8448 (accessed
September 21, 2023).
AMA:
Tan, Su-Fern, Liu, Xin, Fox, Todd E., Barth, Brian M., Sharma, Arati, Turner, Stephen D., Awwad, Andy, Dewey, Alden, Doi, Kenichiro, Spitzer, Barbara, Shah, Mithun Vinod, Morad, Samy A.F., 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. Jr..
Acid ceramidase is upregulated in AML and represents a novel therapeutic target. .
December 2016;
():
.
http://hdl.handle.net/10342/8448. Accessed
September 21, 2023.
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