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

Cheng-Fan Lee, Andrew Dang, Elizabeth Hernandez, Rey-Chen Pong, Benjamin Chen, Rajni Sonavane, Ganesh Raj, Payal Kapur, Hsin-Ying Lin, Shang-Ru Wu, Chun-Jung Ko, U-Ging Lo, Hsin-Yu Lee, Jer-Tsong Hsieh, Ming-Shyue Lee

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5580-5598
Number of pages19
JournalOncogene
Volume38
Issue number28
DOIs
Publication statusPublished - Jul 2019
Externally publishedYes

Keywords

  • Adaptor Proteins, Signal Transducing/metabolism
  • Disease Progression
  • Enzyme Activation
  • Humans
  • Male
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Phosphotransferases (Alcohol Group Acceptor)/metabolism
  • Polysaccharides/pharmacology
  • Prostatic Neoplasms/enzymology
  • Serine Endopeptidases/metabolism
  • Sphingosine-1-Phosphate Receptors/metabolism

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