title: Luteolin induces carcinoma cell apoptosis through binding Hsp90 to suppress constitutive activation of STAT3.
abstract: BACKGROUND
  Abnormal activity of STAT3 is associated with a number of human malignancies. Hsp90 plays a central role in stabilizing newly synthesized proteins and participates in maintaining the functional competency of a number of signaling transducers involved in cell growth, survival and oncogenesis, such as STAT3. Hsp90 interacts with STAT3 and stabilizes Tyr-phosphorylated STAT3. It has been reported that luteolin possesses anticancer activity through degradation of Tyr(705)-phosphorylated STAT3.
  
  
  RESULTS
  We found that overexpression of Hsp90 inhibited luteolin-induced degradation of Tyr(705)-phosphorylated STAT3 and luteolin also reduced the levels of some other Hsp90 interacting proteins. Results from co-immunoprecipitation and immunoblot analysis demonstrated that luteolin prevented the association between Hsp90 and STAT3 and induced both Tyr(705)- and Ser(727)-phosphorylated STAT3 degradation through proteasome-dependent pathway. The molecular modeling analysis with CHARMm-Discovery Studio 2.1(DS 2.1) indicated that luteolin could bind to the ATP-binding pocket of Hsp90. SPR technology-based binding assay confirmed the association between luteolin and Hsp90. ATP-sepharose binding assay displayed that luteolin inhibited Hsp90-ATP binding.
  
  
  CONCLUSIONS
  Luteolin promoted the degradation of Tyr(705)- and Ser(727)-phosphorylated STAT3 through interacting with Hsp90 and induced apoptosis of cancer cells. This study indicated that luteolin may act as a potent HSP90 inhibitor in antitumor strategies.
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Fu
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhao
authors.forename: Jiahong
authors.initials: J
authors.lastname: Zhou
authors.forename: Yimiao
authors.initials: Y
authors.lastname: Xu
authors.forename: Yinqiang
authors.initials: Y
authors.lastname: Xin
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D059748:Proteolysis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018841:HSP90 Heat-Shock Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014443:Tyrosine; D047311:Luteolin