Inhibition of matrix metalloproteinase activity in DU145 human prostate cancer cells by flavonoids from lowbush blueberry (Vaccinium angustifolium): possible roles for protein kinase C and mitogen-activated protein-kinase-mediated events.
Regulation of the matrix metalloproteinases (MMPs) is crucial to regulate extracellular matrix (ECM) proteolysis which is important in metastasis. This study investigated the mechanism(s) by which three flavonoid-enriched fractions from lowbush blueberry (Vaccinium angustifolium) down-regulate MMP activity in DU145 human prostate cancer cells. Metalloproteinase activity was evaluated from cells exposed to "crude," anthocyanin-enriched (AN) and proanthocyanidin-enriched (PAC) fractions. Differential down-regulation of MMPs was observed. The activity of the endogenous tissue inhibitors of metalloproteinases (TIMPs) from these cells was also evaluated. Increases in TIMP-1 and TIMP-2 activity were observed in response to these fractions. The possible involvement of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase pathways in the flavonoid-mediated decreases in MMP activity was observed. These findings indicate that blueberry flavonoids may use multiple mechanisms in down-regulating MMP activity in these cells.
Matchett
Michael D
MD
Department of Biology, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3.
MacKinnon
Shawna L
SL
Sweeney
Marva I
MI
Gottschall-Pass
Katherine T
KT
Hurta
Robert A R
RA
D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011493:Protein Kinase C / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D029796:Vaccinium / Q000737:chemistry*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D011494:Protein Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9