title: Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells.
abstract: OBJECTIVE
  Alterations in ceramide metabolism have been reported in prostate cancer (PCa), resulting in escape of cancer cells from ceramide-induced apoptosis. Specifically, increased expression of lysosomal acid ceramidase (AC) has been shown in some primary PCa tissues and in several PCa cell lines. To determine if this represents a novel therapeutic target, we designed and synthesized LCL204, a lysosomotropic analog of B13, a previously reported inhibitor of AC METHODS: Prostate cancer cell lines were treated with LCL204 for varying times and concentrations. Effects of treatment on cytotoxicity, sphingolipid content, and apoptotic markers were assessed.
  
  
  RESULTS
  Treatment of DU145 PCa cells resulted in increased ceramide and decreased sphingosine levels. Interestingly, LCL204 caused degradation of AC in a cathepsin-dependent manner. We also observed rapid destabilization of lysosomes and the release of lysosomal proteases into the cytosol following treatment with LCL204. Combined, these events resulted in mitochondria depolarization and executioner caspase activation, ultimately ending in apoptosis
  
  
  CONCLUSIONS
  These results provide evidence that treatment with molecules such as LCL204, which restore ceramide levels in PCa cells may serve as a new viable treatment option for PCa.
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29403, USA.
authors: David H
authors: DH
authors: Holman
authors: Lorianne S
authors: LS
authors: Turner
authors: Ahmed
authors: A
authors: El-Zawahry
authors: Saeed
authors: S
authors: Elojeimy
authors: Xiang
authors: X
authors: Liu
authors: Jacek
authors: J
authors: Bielawski
authors: Zdzislaw M
authors: ZM
authors: Szulc
authors: Kristi
authors: K
authors: Norris
authors: Youssef H
authors: YH
authors: Zeidan
authors: Yusuf A
authors: YA
authors: Hannun
authors: Alicja
authors: A
authors: Bielawska
authors: James S
authors: JS
authors: Norris
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D002517:Galactosylgalactosylglucosylceramidase / Q000037:antagonists & inhibitors*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D051336:Mitochondrial Membranes / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013107:Sphingolipids / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D013107:Sphingolipids; D013108:Sphingomyelin Phosphodiesterase; D002517:Galactosylgalactosylglucosylceramidase; D020169:Caspases