title: Altered cross-linking of HSP27 by zerumbone as a novel strategy for overcoming HSP27-mediated radioresistance.
abstract: OBJECTIVE
  HSP27 or HSP25 negatively regulates apoptosis pathways after radiation or chemotherapeutic agents. Abrogation of HSP27 function may be a candidate target for overcoming radio- and chemoresistance.
  
  
  METHODS
  Zerumbone (ZER), a cytotoxic component isolated from Zingiber zerumbet smith. Clonogenic survival assay and flow cytometry after Annexin V staining were performed to determine in vitro sensitization effects of ZER with ionizing radiation. A nude mouse xenografting system was also applied to detect in vivo radiosensitizing effects of ZER.
  
  
  RESULTS
  ZER produced cross-linking of HSP27, which was dependent on inhibition of the monomeric form of HSP27. ZER was directly inserted between the disulfide bond in the HSP27 dimer and modified normal HSP27 dimerization. Pretreatment with ZER before radiation inhibited the binding affinity between HSP27 and apoptotic molecules, such as cytochrome c and PKCδ, and induced sensitization in vitro and in an in vivo xenografted nude mouse system. Structural analogs lacking only the carbonyl group in ZER, such as α-humulene (HUM) and 8-hydroxy-humulen (8-OH-HUM), did not affect normal cross-linking of HSP27 and did not induce radiosensitization.
  
  
  CONCLUSIONS
  We suggest that altered cross-linking of HSP27 by ZER is a good strategy for abolishing HSP27-mediated resistance.
authors.affiliation: Division of Radiation Effects, Korea Institute of Radiological and Medical Science, Seoul, Korea.
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Choi
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Woo Duck
authors.initials: WD
authors.lastname: Seo
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Nam
authors.forename: Yoo Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Seo
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D055551:HSP27 Heat-Shock Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000081222:Monocyclic Sesquiterpenes; D051745:Protein Kinase C-delta / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects* / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D003432:Cross-Linking Reagents; D055551:HSP27 Heat-Shock Proteins; D000081222:Monocyclic Sesquiterpenes; D011838:Radiation-Sensitizing Agents; D012717:Sesquiterpenes; C403304:zerumbone; C042686:humulene; D045304:Cytochromes c; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta