Acid ceramidase-mediated production of sphingosine 1-phosphate promotes prostate cancer invasion through upregulation of cathepsin B

Invasiveness is one of the key features of aggressive prostate cancer; however, our understanding of the precise mechanisms effecting invasion remains limited. The ceramide hydrolyzing enzyme acid ceramidase (AC), overexpressed in most prostate tumors, causes an aggressive and invasive phenotype thr...

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Bibliographic Details
Published in:International journal of cancer Vol. 131; no. 9; pp. 2034 - 2043
Main Authors: Beckham, Thomas H., Lu, Ping, Cheng, Joseph C., Zhao, Dan, Turner, Lorianne S., Zhang, Xiaoyi, Hoffman, Stanley, Armeson, Kent E., Liu, Angen, Marrison, Tucker, Hannun, Yusuf A., Liu, Xiang
Format: Journal Article
Language:English
Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2012
Wiley-Blackwell
Wiley Subscription Services, Inc
Subjects:
acid ceramidase
Acid Ceramidase - metabolism
Biological and medical sciences
Cancer
cathepsin B
Cathepsin B - antagonists & inhibitors
Cathepsin B - genetics
Cathepsin B - metabolism
Cell Line, Tumor
Cell Membrane - metabolism
Cell Movement
Humans
invasion
Lysophospholipids - biosynthesis
Male
Medical research
Medical sciences
Neoplasm Invasiveness
Nephrology. Urinary tract diseases
Promoter Regions, Genetic
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Proto-Oncogene Protein c-ets-1 - metabolism
Sphingosine - analogs & derivatives
Sphingosine - biosynthesis
tumor metastasis
Tumors
Tumors of the urinary system
Up-Regulation
Urinary tract. Prostate gland
Urinary system disease
Prostate disease
Enzyme
Cysteine endopeptidases
Biosynthesis
Metastasis
Malignant tumor
Ceramidase
Invasion
Peptidases
Cancerology
Sphingosine-1-phosphate
Cathepsin B
Hydrolases
tumor metastasis
Male genital diseases
Prostate cancer
Cancer
acid ceramidase
ISSN:0020-7136, 1097-0215, 1097-0215
Online Access:Get full text
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Description
Summary:Invasiveness is one of the key features of aggressive prostate cancer; however, our understanding of the precise mechanisms effecting invasion remains limited. The ceramide hydrolyzing enzyme acid ceramidase (AC), overexpressed in most prostate tumors, causes an aggressive and invasive phenotype through downstream effectors that have not yet been well characterized. Here, we demonstrate that AC, through generation of sphingosine‐1‐phosphate (S1P), promotes Ets1 nuclear expression and binding to the promoter region of matrix‐degrading protease cathepsin B. Through confocal microscopy and flow cytometry, we found that AC overexpression promotes pericellular localization of cathepsin B and its translocation to the outer leaflet of the cell membrane. AC overexpressing cells have an increased abundance of cathepsin B‐enriched invasive structures and enhanced ability to invade through a collagen matrix, but not in the presence of an inhibitor of cathepsin B. In human prostate tissues, AC and cathepsin B overexpression were strongly associated and may relate to poor outcome. These results demonstrate a novel pathway by which AC, through S1P, promotes an invasive phenotype in prostate cancer by causing overexpression and secretion of cathepsin B through activation and nuclear expression of Ets1. As prostate cancer prognosis is dramatically worse when invasion has occurred, this study provides critical insight into the progression toward lethal prostate cancer.
Bibliography:National Institute of Health - No. 5P01CA097132-07
Department of Defense - No. PCTA: PC101962
NIH/NCI - No. PO1 CA97132; No. 1R24CA82933
National Centers for Research Resources - No. UL1RR029882
istex:6CBEE928BBA339B66DBA09FFFBA1943382350BBC
ArticleID:IJC27480
NIH - No. C06 RR015455
ark:/67375/WNG-F635ZW9S-0
National Center For Research Resources - No. UL1RR029882
Tel.: +843‐792‐7412, Fax: +843‐792‐2464
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SourceType-Scholarly Journals-1
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ISSN:0020-7136
1097-0215
1097-0215
DOI:10.1002/ijc.27480