(−)‐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

Abstract

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.

The Role of EGCG in Breast Cancer Prevention and Therapy.

“…EGCG, through inhibition of AP-1 (activator protein-1) and NF-B, suppresses uPA secretion and reduces the metastatic behavior of breast cancer cells [70]. The EGCG derivative 3e could repress metastasis in MDA-MB-231 cells by the same mechanism [71].…”

Licochalcone A Inhibits Cellular Motility by Suppressing E-cadherin and MAPK Signaling in Breast Cancer

“…Apigenin and quercetin have been reported to cause apoptosis, suppress cell proliferation, and increase the generation of reactive oxygen species (ROS) in MDA-MB-231 human breast cancer cells [13,14]. (-)-Epigallocatechin-3-gallate and wogonoside could inhibit the migration and invasion of MDA-MB-231 cells by reducing mitogen-activated protein kinase (MAPK) signaling [15,16]. Moreover, ginkgetin and silibinin could aggravate the dysregulation of mitochondrial function and DNA damage in breast cancer cells [17,18].…”

Anticarcinogenic potentials of tea catechins

“…Urokinase plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) are also associated with ECM degradation and are considered biomarkers for metastasis of cancer cells. GTPs inhibited the uPA secretion and suppressed the metastatic behavior of BC cell malondialdehyde (MDA)-MB-231 by inhibiting activator protein-1 (AP-1) and nuclear factor κB (NF-κB) ( 110 ), in which an EGCG derivative 3e was able to inhibit the expression of both uPA and PAI-1, resulting in inhibition of the cancer cell metastasis ( 111 ). The inhibitive effect of EGCG on the metastasis of prostate cancer cell LNCaP ( 112 ) and the above-mentioned oral cancer cell OC2 ( 103 ) is also involved in the inhibition of uPA expression.…”