Protective effect of quercetin on ER stress caused by calcium dynamics dysregulation in intestinal epithelial cells

Quercetin, one of the flavonoids present in plants, expresses several physiological functions including antioxidative and anti-inflammatory properties. However, its effect on intestinal epithelia remains to be elucidated. Endoplasmic reticulum (ER) stress has been attracting considerable attention since ER stress triggers such disorders as inflammation and cancer. The effect of quercetin on ER stress was investigated in this present study. Several ER stress inducers (tunicamycin, A23187, thapsigargin and brefeldin A) were added to human colonic LS180 cells or Caco-2 cells with quercetin, and the GRP78 expression as an ER stress marker was determined. The results showed that quercetin suppressed the induction of GRP78 expression by these ER stressors, excepting brefeldin A, at both the mRNA and protein levels. Additionally, XBP-1 mRNA splicing was determined to evaluate the activation of IRE1. The phosphorylation of eIF2α and shutdown of protein synthesis were determined to evaluate the activation of PERK. Although quercetin activated IRE1 and PERK when added to LS180 cells alone, it suppressed the activation of IRE1 and PERK induced by A23187 or thapsigargin. The suppressive effect of quercetin on GRP78 mRNA induction was reproduced by PI3K inihibitors (LY294002 and wortmannin), but not by vitamin C and E. LY294002 failed to suppress the GRP78 mRNA induction in combination with quercetin. In conclusion, this study indicates for the first time that quercetin suppressed the ER stress caused by calcium dynamics dysregulation by the inhibition of PI3K. This study helps to clarify the mechanism for quercetin presenting its versatility.