title: Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27.
abstract: It is conceivable that stimulating proteasome activity for rapid removal of misfolded and oxidized proteins is a promising strategy to prevent and alleviate aging-related diseases. Sulforaphane (SFN), an effective cancer preventive agent derived from cruciferous vegetables, has been shown to enhance proteasome activities in mammalian cells and to reduce the level of oxidized proteins and amyloid β-induced cytotoxicity. Here, we report that SFN activates heat shock transcription factor 1-mediated heat shock response. Specifically, SFN-induced expression of heat shock protein 27 (Hsp27) underlies SFN-stimulated proteasome activity. SFN-induced proteasome activity was significantly enhanced in Hsp27-overexpressing cells but absent in Hsp27-silenced cells. The role of Hsp27 in regulating proteasome activity was further confirmed in isogenic REG cells, in which SFN-induced proteasome activation was only observed in cells stably overexpressing Hsp27, but not in the Hsp27-free parental cells. Finally, we demonstrated that phosphorylation of Hsp27 is irrelevant to SFN-induced proteasome activation. This study provides a novel mechanism underlying SFN-induced proteasome activity. This is the first report to show that heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1-Nrf2 pathway, may contribute to cytoprotection.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Nanqin
authors.initials: N
authors.lastname: Gan
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Wu
authors.forename: Mathilde
authors.initials: M
authors.lastname: Brunet
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.forename: Fung-Lung
authors.initials: FL
authors.lastname: Chung
authors.forename: Chengkai
authors.initials: C
authors.lastname: Dai
authors.forename: Lixin
authors.initials: L
authors.lastname: Mi
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects*; D006358:Hot Temperature; D006801:Humans; D015151:Immunoblotting; D017879:Isothiocyanates; D007976:Leupeptins / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D055551:HSP27 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D017879:Isothiocyanates; D007976:Leupeptins; D061988:Proteasome Inhibitors; D013454:Sulfoxides; D013861:Thiocyanates; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex; C016766:sulforaphane; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde