Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells.
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.
Holman
David H
DH
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29403, USA.
Turner
Lorianne S
LS
El-Zawahry
Ahmed
A
Elojeimy
Saeed
S
Liu
Xiang
X
Bielawski
Jacek
J
Szulc
Zdzislaw M
ZM
Norris
Kristi
K
Zeidan
Youssef H
YH
Hannun
Yusuf A
YA
Bielawska
Alicja
A
Norris
James S
JS
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
D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D013107:Sphingolipids; D013108:Sphingomyelin Phosphodiesterase; D002517:Galactosylgalactosylglucosylceramidase; D020169:Caspases