Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP prostate cancer cells to TRAIL-induced apoptosis

Szliszka,Ewelina; Zydowicz,Grzegorz; Mizgala,Elzbieta; Krol,Wojciech

doi:10.3892/ijo.2012.1527

Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) sensitizes LNCaP prostate cancer cells to TRAIL-induced apoptosis

Authors:
- Ewelina Szliszka
- Grzegorz Zydowicz
- Elzbieta Mizgala
- Wojciech Krol
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Affiliations: Department of Microbiology and Immunology, Medical University of Silesia in Katowice, Zabrze, Poland, Department of Family Medicine, Medical University of Silesia in Katowice, Zabrze, Poland
Published online on: June 25, 2012 https://doi.org/10.3892/ijo.2012.1527
Pages: 818-828
Copyright: © Szliszka et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Naturally occurring phenolic compounds have been shown to sensitize prostate cancer cells to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. TRAIL is a potent stimulator of apoptosis in cancer cells and an important immune effector molecule in the surveillance and elimination of developing tumours. However, many cancer cells are resistant to TRAIL-mediated death. In this study, we aimed to determine the mechanisms by which TRAIL resistance can be overcome in prostate cancer cells by 3,5-diprenyl-4-hydroxycinnamic acid (artepillin C). Artepillin C is a bioactive component of Brazilian green propolis that possesses antitumour and chemopreventive activities. TRAIL-resistant LNCaP prostate cancer cells were treated with TRAIL and artepillin C. Cytotoxicity was measured by MTT and lactate dehydrogenase (LDH) assays. Apoptosis was detected using Annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor (DR) (TRAIL-R1/DR4 and TRAIL-R2/DR5) expression was analyzed using flow cytometry. Mitochondrial membrane potential (∆ψm) was evaluated using DePsipher staining by fluorescence microscopy. The inhibition of NF-κB (p65) activation was confirmed with the ELISA-based TransAM NF-κB kit. Caspase-8 and caspase-3 activities were determined by colorimetric protease assays. The results showed that artepillin C sensitized the TRAIL-resistant LNCaP cells by engaging the extrinsic (receptor-mediated) and intrinsic (mitochondrial) apoptotic pathways. Artepillin C increased the expression of TRAIL-R2 and decreased the activity of NF-κB. Co-treatment with TRAIL and artepillin C induced the significant activation of caspase-8 and caspase-3, as well as the disruption of ∆ψm. These findings show that prostate cancer cells can be sensitized to TRAIL-mediated immunoprevention by artepillin C and confirm the role of phenolic compounds in prostate cancer immunochemoprevention.

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