|Title:||Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase||Authors:||Lee, Cheng-Fan
|Issue Date:||2019||Publisher:||Nature Publishing Group||Journal Volume:||38||Journal Issue:||28||Start page/Pages:||5580-5598||Source:||Oncogene||Abstract:||
Gram-negative bacteria have been found to be a major population in prostatitis and prostate cancer (PCa) tissues. Lipopolysaccharide (LPS), a major compound of Gram-negative bacteria, with stimulatory activities in some cancer types, but has not been fully studied in PCa. In this study, we examined the effect of LPS on the invasion of PCa cells. Interestingly, LPS can enhance the invasiveness of PCa, but had no significant effect on PCa cell viability. Using protease inhibitor screening and biochemical analyses, matriptase, a member of the membrane-anchored serine protease family, is found to play a key role in LPS-induced PCa cell invasion. Mechanistically, Toll-like receptor 4 (TLR4, LPS receptor)-sphingosine kinase 1 (SphK1) signaling underlies LPS-induced matriptase activation and PCa cell invasion. Specifically, LPS induced the S225 phosphorylation of SphK1 and the translocation of SphK1 to plasma membrane, leading to the production of sphingosine 1-phosphate (S1P), ERK1/2 and matriptase activation via S1P receptor 4 (S1PR4). This phenomenon is further validated using the patient-derived explant (PDE) model. Indeed, there is a significant correlation among the elevated SphK1 levels, the Gleason grades of PCa specimens, and the poor survival of PCa patients. Taken together, this study demonstrates a potential impact of LPS on PCa progression. Our results provide not only a new finding of the role of bacterial infection in PCa progression but also potential therapeutic target(s) associated with PCa metastasis. ? 2019, The Author(s), under exclusive licence to Springer Nature Limited.
|ISSN:||0950-9232||DOI:||10.1038/s41388-019-0833-3||SDG/Keyword:||bacterium lipopolysaccharide; matriptase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; sphingosine 1 phosphate; sphingosine 1 phosphate receptor; sphingosine 1 phosphate receptor 4; sphingosine kinase; sphingosine kinase 1; toll like receptor 4; unclassified drug; matriptase; phosphotransferase; polysaccharide; serine proteinase; signal transducing adaptor protein; SKIP protein, human; sphingosine kinase; animal experiment; animal model; animal tissue; Article; bacterial infection; biochemical analysis; cancer growth; cancer survival; cell invasion; cell membrane; cell migration; cell viability; controlled study; enzyme activation; enzyme phosphorylation; Gleason score; human; human cell; human tissue; male; metastasis; mouse; NOD SCID mouse; nonhuman; priority journal; prostate cancer; protein expression level; protein transport; recurrence free survival; signal transduction; tumor invasion; upregulation; disease exacerbation; enzyme activation; enzymology; metabolism; metastasis; pathology; prostate tumor; Adaptor Proteins, Signal Transducing; Disease Progression; Enzyme Activation; Humans; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphotransferases (Alcohol Group Acceptor); Polysaccharides; Prostatic Neoplasms; Serine Endopeptidases; Sphingosine-1-Phosphate Receptors
|Appears in Collections:||生物化學暨分子生物學科研究所|
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