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 2 alpha (eIF2 alpha), 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 eIF2 alpha inhibitor, or overexpression of dominant negative mutants of PERK or eIF2 alpha, effectively restored RES-induced cell cycle arrest, underscoring the important role of PERK/eIF alpha branch of UPR in RES-induced inhibition of cell proliferation. (C) 2009 Elsevier Inc. All rights reserved.