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

Lirdprapamongkol,Kriengsak; Sakurai,Hiroaki; Abdelhamed,Sherif; Yokoyama,Satoru; Athikomkulchai,Sirivan; Viriyaroj,Amornrat; Awale,Suresh; Ruchirawat,Somsak; Svasti,Jisnuson; Saiki,Ikuo

doi:10.3892/ijo.2013.1926

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

Authors:
- Kriengsak Lirdprapamongkol
- Hiroaki Sakurai
- Sherif Abdelhamed
- Satoru Yokoyama
- Sirivan Athikomkulchai
- Amornrat Viriyaroj
- Suresh Awale
- Somsak Ruchirawat
- Jisnuson Svasti
- Ikuo Saiki
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Affiliations: Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand, Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan, Faculty of Pharmacy, Srinakharinwirot University, Nakhon Nayok 26120, Thailand, Frontier Research Core for Life Sciences, University of Toyama, Toyama 930-0194, Japan, Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand
Published online on: May 1, 2013 https://doi.org/10.3892/ijo.2013.1926
Pages: 329-337

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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.

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