Crosstalk Between Endoplasmic Reticulum Stress And Oxidative Stress In Apoptosis Induced By Vitamin E Succinate In Human Gastric Carcinoma Cells

Vitamin E succinate (RRR-α-tocopheryl succinate, VES), a derivative of naturalvitamin E, has been shown to be a potent apoptosis inducer and growth inhibitor in avariety of cancer cells. Here we studied the effect of endoplasmic reticulum (ER)stress and unfolded protein response (UPR) on VES-induced apoptosis of SGC-7901human gastric cancer cells. Then we further investigated the interplay betweenendoplasmic reticulum stress (ERS) and oxidative stress induced by VES.We found that VES caused cytological changes typical of apoptosis andincreased ER dilation. And endogenous ER stress markers, glucose-regulated protein78(GRP78) and glucose-regulated protein94(GRP94) were transcriptionally andtranslationally altered. In response to VES, induction of C/EBP homologous proteintranscription factor (CHOP), activation of caspase-4and JNK were observed. VESalso triggered activation of UPR components, including RNA-dependent proteinkinase (PKR)-like ER kinase (PERK), activating transcription factor6(ATF6),X-box-binding protein1(XBP1), and activating transcription factor4(ATF4) in aconcentration-and time-dependent manner. And the antioxidant N-acetyl-L-cysteine(NAC) transcriptionally and translationally inhibited induction of GRP78and CHOPby VES. Furthermore, knocking down CHOP by RNAi decreased reactive oxygenspecies (ROS) generation, increased glutathione (GSH) level and induced glutathioneperoxidase (GPX) mRNA expression in VES-treated cells, whereas catalase (CAT)and superoxide dismutases (SOD) mRNA expression were not altered.Consequently, our results suggest that VES-induced apoptosis is coupled to ERSand UPR activation in SGC-7901human gastric cancer cells. The results also imply VES induces ERS response through ROS production, while CHOP perturbs the redoxstate of SGC-7901cells treated with VES.