A novel approach of proteomics and transcriptomics to study the mechanism of action of the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin-3-gallate.
Previous findings suggest that the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) may have a neurorescue impact in aging and neurodegenerative diseases to retard or even reverse the accelerated rate of neuronal degeneration. The present study sought a deeper elucidation of the molecular neurorescue activity of EGCG in a progressive neurotoxic model of long-term serum deprivation of human SH-SY5Y neuroblastoma cells. In this model, proteomic analysis revealed that EGCG (0.1-1 microM) affected the expression levels of diverse proteins, including proteins related to cytoskeletal components, metabolism, heat shock, and binding. EGCG induced the levels of cytoskeletal proteins, such as beta tubulin IV and tropomyosin 3, playing a role in facilitating cell assembly. In accordance, EGCG increased the levels of the binding protein 14-3-3 gamma, involved in cytoskeletal regulation and signal transduction pathways in neurons. Additionally, EGCG decreased protein levels and mRNA expression of the beta subunit of the enzyme prolyl 4-hydroxylase, which belongs to a family of iron-oxygen sensors of hypoxia-inducible factor (HIF) prolyl hydroxylases that negatively regulate the stability and degradation of several proteins involved in cell survival and differentiation. Accordingly, EGCG decreased protein levels of two molecular chaperones that were associated with HIF regulation, the immunoglobulin-heavy-chain binding protein and the heat shock protein 90 beta. Thus, the present study sheds some light on the antioxidative-iron chelating activities of EGCG underlying its neuroprotective/neurorescue mechanism of action, further suggesting a potential neurodegenerative-modifying effect for EGCG.
Weinreb
Orly
O
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa 31096, Israel.
Amit
Tamar
T
Youdim
Moussa B H
MB
D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D015180:Electrophoresis, Gel, Two-Dimensional; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D059808:Polyphenols; D040901:Proteomics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013662:Tea / Q000737:chemistry; D014158:Transcription, Genetic
D000975:Antioxidants; D005419:Flavonoids; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D010636:Phenols; D010936:Plant Extracts; D059808:Polyphenols; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate