Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response.
BACKGROUND
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. However, the underlying molecular mechanisms are at present only partially understood.


METHODS
The 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.


RESULTS
Similar 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 eIF2alpha 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.


CONCLUSIONS
Our 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.
Yan
Ying
Y
Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110001, China.
Gao
Yan-Yan
YY
Liu
Bao-Qin
BQ
Niu
Xiao-Fang
XF
Zhuang
Ying
Y
Wang
Hua-Qin
HQ
D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D000071701:Regulatory Factor X Transcription Factors; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D051702:Activating Transcription Factor 6; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D000077185:Resveratrol; D013267:Stilbenes; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D014665:Vasodilator Agents; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C000717247:HSPA5 protein, human; C000605543:XBP1 protein, human; C053387:endoplasmin