title: Fisetin, a dietary flavonoid, induces apoptosis of cancer cells by inhibiting HSF1 activity through blocking its binding to the hsp70 promoter.
abstract: Heat shock factor 1 (HSF1) is a transcription factor for heat shock proteins (HSPs) expression that enhances the survival of cancer cells exposed to various stresses. HSF1 knockout suppresses carcinogen-induced cancer induction in mice. Therefore, HSF1 is a promising therapeutic and chemopreventive target. We performed cell-based screening with a natural compound collection and identified fisetin, a dietary flavonoid, as a HSF1 inhibitor. Fisetin abolished heat shock-induced luciferase activity with an IC50 of 14 μM in HCT-116 cancer cells. The treatment of HCT-116 with fisetin inhibited proliferation with a GI50 of 23 μM. When the cells were exposed to heat shock in the presence of fisetin, the induction of HSF1 target proteins, such as HSP70, HSP27 and BAG3 (Bcl-2-associated athanogene domain 3), were inhibited. HSP70/BAG3 complexes protect cancer cells from apoptosis by stabilizing anti-apoptotic Bcl-2 family proteins. The downregulation of HSP70/BAG3 by fisetin significantly reduced the amounts of Bcl-2, Bcl-xL and Mcl-1 proteins, subsequently inducing apoptotic cell death. Chromatin immunoprecipitation assays showed that fisetin inhibited HSF1 activity by blocking the binding of HSF1 to the hsp70 promoter. Intraperitoneal treatment of nude mice with fisetin at 30mg/kg resulted in a 35.7% (P < 0.001) inhibition of tumor growth.
authors.affiliation: Genomics Structure Research Center, Korea Research Institute of Bioscience and Biotechnology and Department of BioMolecular Science, University of Science and Technology in Korea and.
authors.forename: Joo Ae
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Genomics Structure Research Center, Korea Research Institute of Bioscience and Biotechnology and Department of BioMolecular Science, University of Science and Technology in Korea and.
authors.forename: Somyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Genomics Structure Research Center, Korea Research Institute of Bioscience and Biotechnology and Department of BioMolecular Science, University of Science and Technology in Korea and.
authors.forename: Da-Eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Department of BioMolecular Science, University of Science and Technology in Korea and Bio-Nano Research Center, Korea Research Institute of Bioscience and Biotechnology, 111 Gwahangno, Yuseong-gu, Daejeon 305-806, Korea.
authors.forename: Moonil
authors.initials: M
authors.lastname: Kim
authors.affiliation: Genomics Structure Research Center, Korea Research Institute of Bioscience and Biotechnology and Department of BioMolecular Science, University of Science and Technology in Korea and.
authors.forename: Byoung-Mog
authors.initials: BM
authors.lastname: Kwon
authors.affiliation: Genomics Structure Research Center, Korea Research Institute of Bioscience and Biotechnology and Department of BioMolecular Science, University of Science and Technology in Korea and dchan@kribb.re.kr kwonbm@kribb.re.kr.
authors.forename: Dong Cho
authors.initials: DC
authors.lastname: Han
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D045325:HCT116 Cells; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018832:Molecular Chaperones; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D004268:DNA-Binding Proteins; D005419:Flavonoids; D044948:Flavonols; C000619706:HSF1 protein, human; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C579095:MCL1 protein, human; D018832:Molecular Chaperones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051020:bcl-X Protein; C017875:fisetin