Implication of unfolded protein response in resveratrol-induced inhibition of K562 cell proliferation.
Resveratrol (RES), a natural plant polyphenol, is an effective inducer of cell cycle arrest and apoptosis in a variety of carcinoma cell types. In addition, RES has been reported to inhibit tumorigenesis in several animal models suggesting that it functions as a chemopreventive and anti-tumor agent in vivo. The chemopreventive and chemotherapeutic properties associated with resveratrol offer promise for the design of new chemotherapeutic agents. However, the mechanisms by which RES mediates its effects are not yet fully understood. In this study, we showed that RES caused cell cycle arrest and proliferation inhibition via induction of unfolded protein response (UPR) in human leukemia K562 cell line. Treatment of K562 cells with RES induced a number of signature UPR markers, including transcriptional induction of GRP78 and CHOP, phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), ER stress-specific XBP-1 splicing, suggesting the induction of UPR by RES. RES inhibited proliferation of K562 in a concentration-dependent manner. Flow cytometric analyses revealed that K562 cells were arrested in G1 phase upon RES treatment. Salubrinal, an eIF2alpha inhibitor, or overexpression of dominant negative mutants of PERK or eIF2alpha, effectively restored RES-induced cell cycle arrest, underscoring the important role of PERK/eIF2alpha branch of UPR in RES-induced inhibition of cell proliferation.
Liu
Bao-Qin
BQ
Department of Biochemistry & Molecular Biology, China Medical University, Shenyang 110001, China.
Gao
Yan-Yan
YY
Niu
Xiao-Fang
XF
Xie
Ji-Sheng
JS
Meng
Xin
X
Guan
Yifu
Y
Wang
Hua-Qin
HQ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017510:Protein Folding; D019154:Protein Splicing; D000071701:Regulatory Factor X Transcription Factors; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D000077185:Resveratrol; D013267:Stilbenes; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497249:DDIT3 protein, human; C000717247:HSPA5 protein, human; C000605543:XBP1 protein, human