Apple- and Hop-polyphenols Inhibit Porphyromonas Gingivalis-mediated Precursor of Matrix Metalloproteinase 9 Activation and Invasion of Oral Squamous Cell Carcinoma Cells.
J Periodontol. 2016 May 13:1-21. Epub 2016 May 13. PMID: 27177287
BACKGROUND: Recent epidemiological studies have revealed a significant association between periodontitis and oral squamous cell carcinoma (OSCC). Furthermore, periodontitis is markedly associated with orodigestive cancer mortality, while Porphyromonas gingivalis infection has been identified as a specific and potentially independent microbial factor related to increased risk of orodigestive cancer death. We previously reported that P. gingivalis induced the precursor form of matrix metalloproteinase 9 (proMMP9) production via proteinase activated receptor (PAR)-related pathways, after which proMMP9 was activated by gingipains to enhance cellular invasion of SAS cells. In the present study, we examined the effects of selected polyphenols as inhibitors of cellular invasion caused by P. gingivalis gingipains in SAS cells.
METHODS: OSCC cells were infected with P. gingivalis strains including gingipain mutants. To evaluate the effects of inhibitors, apple polyphenol (AP), hop bract polyphenol (HBP), high and low molecular weight fractions of HBP (HMW-HBP and LMW-HBP), epigallocatechin gallate (EGCg), KYT-1 (Arg-gingipain inhibitor), and KYT-36 (Lys-gingipain inhibitor) were used. Proteinase activated receptor 2 (PAR2) and PAR4 mRNA expressions were examined using real-time reverse transcription polymerase chain reaction, and signaling pathways were evaluated by western blotting analysis.
RESULTS: KYT-1/KYT-36, AP, HBP, and HMW-HBP significantly inhibited PAR2 and PAR4 mRNA expressions, proMMP9 activation, and cellular invasion. Furthermore, AP, HBP, and HMW-HBP reduced activation of HSP27 and Ets1 and nuclear translocation of NF-kB, whereas EGCg and LMW-HBP did not.
CONCLUSION: These results suggest that AP, HBP, and HMW-HBP are potent inhibitors of proMMP9 activation and cellular invasion mediated with P. gingivalis in OSCC cells.