(-)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78.
Many beneficial properties have been attributed to (-)-epigallocatechin gallate (EGCG), including chemopreventive, anticarcinogenic, and antioxidant actions. In this study, we investigated the effects of EGCG on the function of glucose-regulated 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 drug-treated cancer cells, contributing to the development of drug resistance.
Ermakova
Svetlana P
SP
Hormel Institute, University of Minnesota, Austin, Minnesota.
Kang
Bong Seok
BS
Choi
Bu Young
BY
Choi
Hong Seok
HS
Schuster
Todd F
TF
Ma
Wei-Ya
WY
Bode
Ann M
AM
Dong
Zigang
Z
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy; D053179:Caspase 7 / Q000378:metabolism; D061945:Caspase Inhibitors; D002392:Catechin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005047:Etoposide / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism
D061945:Caspase Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D005047:Etoposide; D002392:Catechin; C045651:epigallocatechin gallate; D053179:Caspase 7; D000251:Adenosine Triphosphatases