The inhibitory effect of hesperidin on tumor cell invasiveness occurs via suppression of activator protein 1 and nuclear factor-kappaB in human hepatocellular carcinoma cells.
Hesperidin (HES) has been reported to exhibit anti-invasive and antimetastatic activities by suppressing the enzymatic activity of matrix metalloproteinase-9 (MMP-9). However, the underlying mechanism of anti-invasive activity remains unclear so far. First, we suggest that the expression of MMP-9 by TPA involves phosphorylation of IKK, p38, and PKC in hepG2. We also demonstrate that hesperidin reduced 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibited the secreted and cytosolic MMP-9 forms in HepG2 cells. Hesperidin significantly suppressed the TPA-induced the mRNA level of MMP-9. Hesperidin suppressed MMP-9 transcription by inhibiting nuclear factor-kappaB (NF-kappaB) and Activator protein 1 (AP-1) activity. Hesperidin suppressed TPA-stimulated NF-kappaB translocation into the nucleus through IkappaB inhibitory signaling pathways and also inhibited TPA-induced AP-1 activity by the inhibitory phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) signaling pathways. In conclusion, Hesperidin might be a potent antiinvasive agent that suppresses the MMP-9 enzymatic activity via NF-kappaB an AP-1 signaling pathway.
Lee
Kuo-Hua
KH
Hsin-Chu Branch Station, Council of Agriculture-TLI, Hsin-Chu, Taiwan.
Yeh
Ming-Hsien
MH
Kao
Shung-Te
ST
Hung
Che-Ming
CM
Liu
Ching-Ju
CJ
Huang
Yung-Yu
YY
Yeh
Chia-Chou
CC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006569:Hesperidin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D006569:Hesperidin; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate