title: Sulforaphane inhibits pancreatic cancer through disrupting Hsp90-p50(Cdc37) complex and direct interactions with amino acids residues of Hsp90.
abstract: Sulforaphane [1-isothiocyanato-4-(methyl-sulfinyl) butane)], an isothiocyanate derived from cruciferous vegetables, has been shown to possess potent chemopreventive activity. We analyzed the effect of sulforaphane on the proliferation of pancreatic cancer cells. Sulforaphane inhibited pancreatic cancer cell growth in vitro with IC(50)s of around 10-15 μM and induced apoptosis. In pancreatic cancer xenograft mouse model, administration of sulforaphane showed remarkable inhibition of tumor growth without apparent toxicity noticed. We found that sulforaphane induced the degradation of heat shock protein 90 (Hsp90) client proteins and blocked the interaction of Hsp90 with its cochaperone p50(Cdc37) in pancreatic cancer cells. Using nuclear magnetic resonance spectroscopy (NMR) with an isoleucine-specific labeling strategy, we overcame the protein size limit of conventional NMR and studied the interaction of sulforaphane with full-length Hsp90 dimer (170 kDa) in solution. NMR revealed multiple chemical shifts in sheet 2 and the adjacent loop in Hsp90 N-terminal domain after incubation of Hsp90 with sulforaphane. Liquid chromatography coupled to mass spectrometry further mapped a short peptide in this region that was tagged with sulforaphane. These data suggest a new mechanism of sulforaphane that disrupts protein-protein interaction in Hsp90 complex for its chemopreventive activity.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, MI, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: G Elif
authors.initials: GE
authors.lastname: Karagöz
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Seo
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yanke
authors.initials: Y
authors.lastname: Yu
authors.forename: Afonso M S
authors.initials: AM
authors.lastname: Duarte
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schwartz
authors.forename: Rolf
authors.initials: R
authors.lastname: Boelens
authors.forename: Kate
authors.initials: K
authors.lastname: Carroll
authors.forename: Stefan G D
authors.initials: SG
authors.lastname: Rüdiger
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects; D018833:Chaperonins / Q000378:metabolism*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011487:Protein Conformation; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D017879:Isothiocyanates; D018832:Molecular Chaperones; D013454:Sulfoxides; D013861:Thiocyanates; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex; D018833:Chaperonins; C016766:sulforaphane