Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response

Ying Yan,Yan-Yan Gao,Bao-Qin Liu,Hua-Qin Wang,Xiao-Fang Niu,Ying Zhuang

doi:10.1186/1471-2407-10-445

Abstract

BackgroundResveratrol (RES), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. However, the underlying molecular mechanisms are at present only partially understood.MethodThe effects of RES on activation of unfolded protein responses (UPR) were evaluated using Western blotting, semi-quantitative and real-time RT-PCR. Cell death was evaluated using Annexin V/PI staining and subsequent FACS.ResultsSimilar as tunicamycin, treatment with RES lead to the activation of all 3 branches of the UPR, with early splicing of XBP-1 indicative of IRE1 activation, phosphorylation of eIF2α consistent with ER resident kinase (PERK) activation, activating transcription factor 6 (ATF6) splicing, and increase in expression levels of the downstream molecules GRP78/BiP, GRP94 and CHOP/GADD153 in human Burkitt's lymphoma Raji and Daudi cell lines. RES was shown to induce cell death, which could be attenuated by thwarting upregulation of CHOP.ConclusionsOur data suggest that activation of the apoptotic arm of the UPR and its downstream effector CHOP/GADD153 is involved, at least in part, in RES-induced apoptosis in Burkitt's lymphoma cells.

Highlights

Resveratrol (RES), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines
Our data suggest that activation of the apoptotic arm of the unfolded protein responses (UPR) and its downstream effector CHOP/GADD153 is involved, at least in part, in RES-induced apoptosis in Burkitt’s lymphoma cells
Our results demonstrate that a proportion of the ability of RES to kill Burkitt’s lymphoma Raji and Daudi cells has been attributed to upregulation of CHOP/GADD153

Summary

Introduction

Resveratrol (RES), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. RES is normally present in many dietary products such as grapes, peanuts, berries and wine [2,3], which is known to affect a broad range of intracellular mediators involved in the initiation, promotion and progression of cancer [3,4,5]. Induction of CHOP/GADD153, one of the components of the ER stress-mediated apoptosis pathway, was shown to be implicated in RES-induced apoptosis in colon cancer cells [17]. UPR could be a potential mechanism of RES cytotoxicity

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Conclusion