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Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase

Oncogene volume 38, pages 5580–5598 (2019)Cite this article

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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.

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Acknowledgements

This work was supported in part by grants from the United States Army (W81XWH-11-1-0491 and W81XWH-16-1-0474) to Jer-Tsong Hsieh, and by Taiwan National Science Council Grant NSC 100-2628-B-002-004-MY4, Ministry of Science and Technology Grants (MOST 103-2321-B-002-096, MOST 104-2320-B-002-044- MY3, MOST 104-2911-I-002-578, MOST 105-2911-I-002-521 and MOST 106-2320-B-002-046-MY3), National Health Research Institutes Grant (NHRI-EX102-9909BC and NHRI-EX106-10401BI), and National Taiwan University Grant NTU-CESRP-104R7602C4 and 107L890504 to Ming-Shyue Lee. We thank Dr. Bink W. Wattenberg at James Graham Brown Cancer Center for SphK1 plasmid, Dr. Ming-Fong Lin at the University of Nebraska Medical Center for human prostate cancer cell lines, Dr. Chen-Yong Lin at the Georgetown University for his gifts of antibodies and I-Wen Huang and Kuan-Jin Yu for their technical supports.

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  1. Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Cheng-Fan Lee, Hsin-Ying Lin, Shang-Ru Wu, Chun-Jung Ko & Ming-Shyue Lee

  2. Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Cheng-Fan Lee, Andrew Dang, Elizabeth Hernandez, Rey-Chen Pong, Rajni Sonavane, Ganesh Raj, U-Ging Lo & Jer-Tsong Hsieh

  3. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Benjamin Chen

  4. Urology and Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Payal Kapur

  5. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Chun-Jung Ko

  6. Department of Life Science, National Taiwan University, Taipei, Taiwan

    Hsin-yu Lee

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Lee, CF., Dang, A., Hernandez, E. et al. Activation of sphingosine kinase by lipopolysaccharide promotes prostate cancer cell invasion and metastasis via SphK1/S1PR4/matriptase. Oncogene 38, 5580–5598 (2019). https://doi.org/10.1038/s41388-019-0833-3

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