Luteolin induces carcinoma cell apoptosis through binding Hsp90 to suppress constitutive activation of STAT3

PLoS One. 2012;7(11):e49194. doi: 10.1371/journal.pone.0049194. Epub 2012 Nov 8.

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.

Methodology/principal findings: 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/significance: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma* / metabolism
  • Carcinoma* / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins* / genetics
  • HSP90 Heat-Shock Proteins* / metabolism
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Luteolin / pharmacology*
  • Mice
  • Neoplasms* / genetics
  • Neoplasms* / metabolism
  • Phosphorylation
  • Protein Binding
  • Proteolysis
  • STAT3 Transcription Factor* / genetics
  • STAT3 Transcription Factor* / metabolism
  • Signal Transduction
  • Tyrosine / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • HSP90 Heat-Shock Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Tyrosine
  • Luteolin

Grants and funding

This work was supported by grants from the National Nature Science Foundation of China (Nos. 81172798, 81072433 and 31071000 ), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No.164320H106), and Jiangsu Major Nature Science Foundation of High Education (No. 12KJA180006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.