title: Inhibition of glycoprotein synthesis in the endoplasmic reticulum as a novel anticancer mechanism of (-)-epigallocatechin-3-gallate.
abstract: (-)-Epigallocatechin-3-gallate (EGCG) has been found to trigger the unfolded protein response (UPR) likely due to the inhibition of glucosidase II, a key enzyme of glycoprotein processing and quality control in the endoplasmic reticulum (ER). These findings strongly suggest that EGCG interferes with glycoprotein maturation and sorting in the ER. This hypothesis was tested in SK-Mel28 human melanoma cells by assessing the effect of EGCG and deoxynojirimycin (DNJ) on the synthesis of two endogenous glycoproteins. Both tyrosinase and vascular endothelial growth factor (VEGF) protein levels were remarkably reduced despite unaltered mRNA expression in EGCG- or DNJ-treated cells compared to control. The hindrance of tyrosinase and VEGF protein synthesis could be prevented by proteasome inhibitor, lactacystine. Collectively, our results support that glucosidase II inhibitor EGCG interferes with protein processing and quality control in the ER, which diverts tyrosinase, VEGF, and likely other glycoproteins towards proteasomal degradation. This mechanism provides a novel therapeutic approach in dermatology and might play an important role in the antitumor effect or hepatotoxicity of EGCG.
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University & MTA-SE Pathobiochemistry Research Group, Budapest, Hungary.
authors.forename: Laura
authors.initials: L
authors.lastname: Konta
authors.forename: Péter
authors.initials: P
authors.lastname: Száraz
authors.forename: Judit É
authors.initials: JÉ
authors.lastname: Magyar
authors.forename: Katalin
authors.initials: K
authors.lastname: Révész
authors.forename: Gábor
authors.initials: G
authors.lastname: Bánhegyi
authors.forename: József
authors.initials: J
authors.lastname: Mandl
authors.forename: Miklós
authors.initials: M
authors.lastname: Csala
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D053140:Organelle Shape / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D059748:Proteolysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006023:Glycoproteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D002392:Catechin; C045651:epigallocatechin gallate; D014442:Monophenol Monooxygenase; D046988:Proteasome Endopeptidase Complex