(−)−Epigallocatechin Gallate Overcomes Resistance to Etoposide-Induced Cell Death by Targeting the Molecular Chaperone Glucose-Regulated Protein 78

Abstract

Many beneficial properties have been attributed to (À)Àepi-gallocatechin gallate (EGCG), including chemopreventive, anticarcinogenic, and antioxidant actions. In this study, we investigated the effects of EGCG on the function of glucoseregulated protein 78 (GRP78), which is associated with the multidrug resistance phenotype of many types of cancer cells. Our investigation was directed at elucidating the mechanism of the EGCG and GRP78 interaction and providing evidence about whether EGCG modulates the activity of anticancer drugs through the inhibition of GRP78 function. We found that EGCG directly interacted with GRP78 at the ATP-binding site of protein and regulated its function by competing with ATP binding, resulting in the inhibition of ATPase activity. EGCG binding caused the conversion of GRP78 from its active monomer to the inactive dimer and oligomer forms. Further, we showed that EGCG interfered with the formation of the antiapoptotic GRP78-caspase-7 complex, which resulted in an increased etoposide-induced apoptosis in cancer cells. We also showed that EGCG significantly suppressed the transformed phenotype of breast cancer cells treated with etoposide. Overall, these results strongly suggested that EGCG could prevent the antiapoptotic effect of GRP78, which usually suppresses the caspase-mediated cell death pathways in drugtreated cancer cells, contributing to the development of drug resistance. (Cancer Res 2006; 66(18): 9260-9)

Inhibition of carcinogenesis by tea constituents

“…Inhibition of telomerase and matrix metalloproteinases has been demonstrated with rather low concentrations of EGCG (IC 50 in the range of 0.5-1 μM). EGCG has also been found to bind to 67-kDa laminin receptor, Bcl-2, vimentin, and glucose-regulated protein 78 with high affinity [50][51][52][53]. However, there are big differences between the effective concentrations determined with pure enzymes and those in cell lines or tissues, possibly due to the nonspecific binding of EGCG to many proteins and the limited amount of EGCG that can enter the cells.…”

Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy

“…GRP78/BiP alleviates ER stress-associated apoptosis by folding ER protein, maintaining ER integrity, and preventing apoptosis. 11,27 In addition to its aforementioned properties, GRP78 acts as an obligatory component of the autophagy pathway in mammalian cells. 11,27,33 However, the cytoprotective role of GRP78-linked autophagy remains unclear.…”

High Ki67, Bax, and thymidylate synthase expression well correlates with response to chemoradiation therapy in locally advanced rectal cancers: proposal of a logistic model for prediction

“…Glucose-regulated protein 78 may confer resistance against adriamycin-and etoposide-mediated apoptosis in cancer cells through inhibition of Bax and caspase-7 activation (Reddy et al, 2003;Davidson et al, 2005;Ermakova et al, 2006;Lee et al, 2006;Ranganathan et al, 2006).…”