Black tea polyphenol (theaflavin) downregulates MMP-2 in human melanoma cell line A375 by involving multiple regulatory molecules.
The tumor-inhibiting property of black tea polyphenol, theaflavin, is well documented. Matrix metalloproteinases (MMPs) play a pivotal role in tumor invasion through degradation of extracellular matrix (ECM). In the present study, we observed the effect of theaflavin on MMP-2, which is upregulated in most tumor types, and its regulatory molecules, in human melanoma cell line, A375. The treatment of theaflavin downregulated the gelatinolytic activity, mRNA and protein expression of MMP-2. It reduced the mRNA and protein expression of membrane type-1 MMP (MT1-MMP) and induced mRNA and protein expression of tissue inhibitor of MMP-2 (TIMP-2), suggesting theaflavin's inhibitory effect on MMP-2 activation. Theaflavin reduced the binding of A375 cell to ECM ligands demonstrating that theaflavin treatment hinders cell-ECM adhesion, cell motility, and integrin-mediated MMP-2 activation. Theaflavin treatment inhibited the protein expression FAK EGFR and ERK, suggesting that, theaflavin treatment downregulates the molecules participating in MMP-2 secretion and regulation. The downregulation of NFchiB suggests downregulation of MMP-2 transactivation. Theaflavin also reduced the tumor volume in syngenic black mice. Thus, we report that theaflavin causes an inhibition of the expression and activity of pro-MMP-2 by a process involving multiple regulatory molecules in human melanoma cells, A375.
Department of Receptor Biology & Tumor Metastasis, Chittaranjan National Cancer, Institute, 37, S P Mukherjee Road, Kolkata - 700 026, West Bengal, India.
Hrishikesh
H
Sil
Triparna
T
Sen
Shuvojit
S
Moulik
Amitava
A
Chatterjee
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D044946:Biflavonoids / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005809:Genes, Regulator / Q000187:drug effects; D006801:Humans; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010936:Plant Extracts / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013662:Tea / Q000737:chemistry*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D044946:Biflavonoids; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D010936:Plant Extracts; D012333:RNA, Messenger; D013662:Tea; D019716:Tissue Inhibitor of Metalloproteinase-2; C056068:theaflavin; D002392:Catechin; D020778:Matrix Metalloproteinase 2