Acid Ceramidase in Melanoma: EXPRESSION, LOCALIZATION, AND EFFECTS OF PHARMACOLOGICAL INHIBITION

Acid ceramidase (AC) is a lysosomal cysteine amidase that controls sphingolipid signaling by lowering the levels of ceramides and concomitantly increasing those of sphingosine and its bioactive metabolite, sphingosine 1-phosphate. In the present study, we evaluated the role of AC-regulated sphingoli...

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Bibliographic Details
Published in:The Journal of biological chemistry Vol. 291; no. 5; pp. 2422 - 2434
Main Authors: Realini, Natalia, Palese, Francesca, Pizzirani, Daniela, Pontis, Silvia, Basit, Abdul, Bach, Anders, Ganesan, Anand, Piomelli, Daniele
Format: Journal Article
Language:English
Published: United States 29.01.2016
Subjects:
Acid Ceramidase - metabolism
Cell Line, Tumor
Cell Proliferation
Cell Survival
Ceramides - chemistry
Down-Regulation
Enzyme Inhibitors - chemistry
Fibroblasts - metabolism
Gene Expression Regulation, Neoplastic
HCT116 Cells
Hep G2 Cells
Humans
Inhibitory Concentration 50
Keratinocytes - metabolism
Lipids - chemistry
Lysophospholipids - metabolism
MCF-7 Cells
Melanocytes - cytology
Melanocytes - metabolism
Melanoma - metabolism
Microscopy, Confocal
Microscopy, Fluorescence
Oxidoreductases - metabolism
RNA, Small Interfering - metabolism
Serine C-Palmitoyltransferase - metabolism
Signal Transduction
Skin Neoplasms - metabolism
Sphingolipids - metabolism
Sphingosine - analogs & derivatives
Sphingosine - metabolism
Uracil - analogs & derivatives
Uracil - chemistry
melanoma
ceramide
cancer biology
enzyme inhibitor
sphingolipid
acid ceramidase
ISSN:1083-351X
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Summary:Acid ceramidase (AC) is a lysosomal cysteine amidase that controls sphingolipid signaling by lowering the levels of ceramides and concomitantly increasing those of sphingosine and its bioactive metabolite, sphingosine 1-phosphate. In the present study, we evaluated the role of AC-regulated sphingolipid signaling in melanoma. We found that AC expression is markedly elevated in normal human melanocytes and proliferative melanoma cell lines, compared with other skin cells (keratinocytes and fibroblasts) and non-melanoma cancer cells. High AC expression was also observed in biopsies from human subjects with Stage II melanoma. Immunofluorescence studies revealed that the subcellular localization of AC differs between melanocytes (where it is found in both cytosol and nucleus) and melanoma cells (where it is primarily localized to cytosol). In addition to having high AC levels, melanoma cells generate lower amounts of ceramides than normal melanocytes do. This down-regulation in ceramide production appears to result from suppression of the de novo biosynthesis pathway. To test whether AC might contribute to melanoma cell proliferation, we blocked AC activity using a new potent (IC50 = 12 nM) and stable inhibitor. AC inhibition increased cellular ceramide levels, decreased sphingosine 1-phosphate levels, and acted synergistically with several, albeit not all, antitumoral agents. The results suggest that AC-controlled sphingolipid metabolism may play an important role in the control of melanoma proliferation.
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ISSN:1083-351X
DOI:10.1074/jbc.M115.666909