Targeting Acid Ceramidase Inhibits Glioblastoma Cell Migration through Decreased AKT Signaling

Cells

Ninh Doan¹  Sajina Gc²  Sasanka Ramanadham²  Sarah E. Williford²  Catherine J. Landis²  Amber B. Jones²  Cyntanna C. Hawkins²  Anita B. Hjelmeland²  Yuvika Harsh²  David K. Crossman³  Julia K. Ziebro⁴  Emily R. Gordon⁵  Sara J. Cooper⁵ 

[1] Baptist South Medical Center, Montgomery, AL 36116, USA;Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, USA;Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA;Graduate Biomedical Sciences, Division of Neuropathology, Department of Pathology, O’Neal Comprehensive Cancer Center, University of Alabama School of Medicine, Birmingham, AL 35233, USA;HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA;

关键词: glioblastoma;    acid ceramidase;    migration;    ceramides;    AKT;   

DOI  :  10.3390/cells11121873

来源: DOAJ

【 摘 要 】

Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the ceramidases which hydrolyze ceramides, acid ceramidase (ASAH1) is highly expressed in GBM samples compared to non-tumor brain. ASAH1 expression also correlates with genes associated with migration and focal adhesion. To understand the role of ASAH1 in GBM migration, we utilized shRNA knockdown and observed decreased migration that did not depend upon changes in growth. Next, we inhibited ASAH1 using carmofur, a clinically utilized small molecule inhibitor. Inhibition of ASAH1 by carmofur blocks in vitro migration of U251 (GBM cell line) and GBM cells derived from patient-derived xenografts (PDXs). RNA-sequencing suggested roles for carmofur in MAPK and AKT signaling. We found that carmofur treatment decreases phosphorylation of AKT, but not of MAPK. The decrease in AKT phosphorylation was confirmed by shRNA knockdown of ASAH1. Our findings substantiate ASAH1 inhibition using carmofur as a potential clinically relevant treatment to advance GBM therapeutics, particularly due to its impact on migration.

【 授权许可】

Unknown