Combined treatment with verrucarin A and tumor necrosis factor-α sensitizes apoptosis by overexpression of nuclear factor-kappaB-mediated Fas

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Title
Combined treatment with verrucarin A and tumor necrosis factor-α sensitizes apoptosis by overexpression of nuclear factor-kappaB-mediated Fas
Author(s)
R G P T Jayasooriya; D O Moon; S R Park; Y H Choi; Y Asami; Mun-Ock KimJae-Hyuk JangBo Yeon KimJong Seog Ahn; G Y Kim
Bibliographic Citation
Environmental Toxicology and Pharmacology, vol. 36, no. 2, pp. 303-310
Publication Year
2013
Abstract
Verrucarin A (VA) is a member of the family of macrocyclic trichothecenes, which exhibit anti-cancer and immune-modulating activities. However, VA has not yet been demonstrated to be involved in the sensitization of tumor necrosis factor-alpha (TNF-α)-mediated apoptosis. In the present study, we found that VA triggers TNF-α-induced apoptosis in human breast cancer MDA-MB-231 and MCF-7 cells. In particular, activation of caspas-3 and caspase-8 as well as release of cytochrome c were significantly enhanced in response to the combined treatment with VA and TNF-α (VA/TNF-α) and the pan-caspase inhibitor z-VAD-fmk completely reversed the apoptosis, suggesting that caspases are the main effector molecules in VA/TNF-α-induced apoptosis via the intrinsic and extrinsic pathway. Moreover, we confirmed that enhanced Fas expression plays a critical role, because the Fas-blocking antibody partially inhibited VA/TNF-α-induced apoptosis. VA also increased specific DNA-binding activity of nuclear factor-kappaB (NF-κB) via nuclear translocation of p50 and p65. In addition, pretreatment with the NF-κB inhibitor MG132 blocked VA/TNF-α-induced apoptosis by suppression of NF-κB-dependent Fas expression. These results indicated that VA enhances TNF-α-induced apoptosis via NF-κB-dependent Fas overexpression.
Keyword
ApoptosisFasNuclear factor-kappaBTumor necrosis factor-αVerrucarin A
ISSN
1382-6689
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.etap.2013.04.008
Type
Article
Appears in Collections:
Ochang Branch Institute > Natural Medicine Research Center > 1. Journal Articles
Ochang Branch Institute > Anticancer Agent Research Center > 1. Journal Articles
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