Chrysin overcomes TRAIL resistance of cancer cells through Mcl-1 downregulation by inhibiting STAT3 phosphorylation

Int J Oncol. 2013 Jul;43(1):329-37. doi: 10.3892/ijo.2013.1926. Epub 2013 May 1.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various types of cancer cells without harming normal cells, but TRAIL resistance has been frequently observed in cancer cells. Propolis (bee glue) is a material collected from various plants by honeybees and is a rich source of bioactive compounds, including the natural flavonoid chrysin, which possesses multiple anticancer effects. We investigated the mechanism underlying the TRAIL sensitization effect of chrysin, which is a major constituent of Thai propolis, in human lung and cervical cancer cell lines. Propolis extract and chrysin sensitizes A549 and HeLa human cancer cell lines to TRAIL-induced apoptosis. The TRAIL sensitization effect of chrysin is not mediated by inhibition of TRAIL-induced NF-κB activation or by glutathione depletion. Immunoblot analysis using a panel of anti-apoptotic proteins revealed that chrysin selectively decreases the levels of Mcl-1 protein, by downregulating Mcl-1 gene expression as determined by qRT-PCR. The contribution of Mcl-1 in TRAIL resistance was confirmed by si-Mcl-1 knockdown. Among signaling pathways that regulate Mcl-1 gene expression, only constitutive STAT3 phosphorylation was suppressed by chrysin. The proposed action of chrysin in TRAIL sensitization by inhibiting STAT3 and downregulating Mcl-1 was supported by using a STAT3‑specific inhibitor, cucurbitacin-I, which decreased Mcl-1 levels and enhanced TRAIL-induced cell death, similar to that observed with chrysin treatment. In conclusion, we show the potential of chrysin in overcoming TRAIL resistance of cancer cells and elucidate its mechanism of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Flavonoids / administration & dosage
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Glutathione / metabolism
  • HeLa Cells
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein / biosynthesis*
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • NF-kappa B / metabolism
  • Phosphorylation
  • Propolis / administration & dosage
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / administration & dosage
  • TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology

Substances

  • Flavonoids
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • chrysin
  • Propolis
  • Glutathione