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(−)‐Epigallocatechin gallate derivatives reduce the expression of both urokinase plasminogen activator and plasminogen activator inhibitor‐1 to inhibit migration, adhesion, and invasion of MDA ‐ MB ‐231 cells
Author(s) -
Shin Sunhye,
Kim Mi Kyoung,
Jung Woong,
Chong Youhoon
Publication year - 2018
Publication title -
phytotherapy research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.019
H-Index - 129
eISSN - 1099-1573
pISSN - 0951-418X
DOI - 10.1002/ptr.6154
Subject(s) - chemistry , protein kinase b , plasminogen activator inhibitor 1 , plasminogen activator , mapk/erk pathway , pi3k/akt/mtor pathway , cancer research , tissue plasminogen activator , urokinase receptor , activator (genetics) , kinase , microbiology and biotechnology , signal transduction , biochemistry , biology , endocrinology , cell , receptor
Urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor‐1 (PAI‐1) are established independent biomarkers for high metastasis risk in breast cancer. In this study, we investigated the regulatory activity of (−)‐epigallocatechin‐3‐gallate (EGCG) and its derivatives on uPA and PAI‐1 expression and thereby their anti‐metastatic potential. EGCG showed only marginal effects on the uPA system and on the metastatic behavior of breast cancer cells (MDA‐MB‐231). However, the EGCG derivative 3e with a methyl‐substituted carbonate substituent at the 4″‐position showed potent inhibition of PAI‐1 (62%) and uPA (50%) expression. The Ras‐extracellular‐signal‐regulated kinase (ERK), p38 mitogen‐activated protein kinase (MAPK), and phosphatidylinositol‐3‐kinase (PI3K)/Akt/NF‐κB pathways, which regulate uPA and PAI‐1 expression, were also affected by 3e (25%, 45%, and 25% reduction, respectively). In line with these findings, substantial reduction in metastatic behavior of MDA‐MB‐231 cells, such as adhesion (40%), invasion (56%), and migration (40%), was observed in the presence of 3e . It is also noteworthy that, in MDA‐MB‐231 cells, 3e did not exert any beneficial effect on the expression of matric metalloprotein (MMP) 2 and 9, which indicates that the anti‐metastatic activity of 3e in MDA‐MB‐231 cells is not related to its regulation of the expression of MMPs. Taken together, we have shown that the EGCG derivative 3e could suppress the metastatic behavior of MDA‐MB‐231 cells through regulation of uPA and PAI‐1.