Journal
ONCOGENE
Volume 38, Issue 28, Pages 5580-5598Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-019-0833-3
Keywords
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Funding
- United States Army [W81XWH-11-1-0491, W81XWH-16-1-0474]
- Taiwan National Science Council [NSC 100-2628-B-002-004-MY4]
- National Health Research Institutes Grant [NHRI-EX102-9909BC, NHRI-EX106-10401BI]
- National Taiwan University [NTU-CESRP-104R7602C4, 107L890504]
- Ministry of Science and Technology [MOST 103-2321-B-002-096, MOST 104-2320B-002-044- MY3, MOST 104-2911-I-002-578, MOST 105-2911-I-002-521, MOST 106-2320-B-002-046-MY3]
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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.
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