Original Article

Cancer Chemotherapy and Pharmacology

, Volume 61, Issue 2, pp 231-242

First online:

Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells

  • David H. HolmanAffiliated withDepartment of Microbiology and Immunology, Medical University of South Carolina
  • , Lorianne S. TurnerAffiliated withDepartment of Microbiology and Immunology, Medical University of South Carolina
  • , Ahmed El-ZawahryAffiliated withDepartment of Microbiology and Immunology, Medical University of South Carolina
  • , Saeed ElojeimyAffiliated withDepartment of Microbiology and Immunology, Medical University of South Carolina
  • , Xiang LiuAffiliated withDepartment of Microbiology and Immunology, Medical University of South Carolina
  • , Jacek BielawskiAffiliated withDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina
  • , Zdzislaw M. SzulcAffiliated withDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina
  • , Kristi NorrisAffiliated withBiochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health
  • , Youssef H. ZeidanAffiliated withDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina
    • , Yusuf A. HannunAffiliated withDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina
    • , Alicja BielawskaAffiliated withDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina
    • , James S. NorrisAffiliated withDepartment of Microbiology and Immunology, Medical University of South Carolina Email author 

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Abstract

Purpose

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.

Keywords

Ceramide Lysosomes Apoptosis LCL204 B13 Acid ceramidase inhibitors