Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells
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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
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.
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
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.
KeywordsCeramide Lysosomes Apoptosis LCL204 B13 Acid ceramidase inhibitors
Hormone-refractory prostate cancer
Lysosomal membrane permeabilization
We thank Rick Peppler of the MUSC Flow Cytometry Facility for acquisition of flow cytometry data. We would also like to thank the MUSC Lipidomics Core for the synthesis of sphingolipid reagents and sphingolipid analysis. This work was supported by NIH/NCI PO1 CA97132 and HCC/DOD N6311601MD10004.
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