Abstract 3200: Acidic microenvironment activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells

Abstract The tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (“Warburg effect”), and defective vasculature that is inefficient to deliver oxygen and nutrients and to remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4, a member of the proton-sensing G protein-coupled receptors, has high expression in endothelial cells. We have previously reported that acidosis induces a broad inflammatory response in human vascular endothelial cells through the GPR4 receptor. Acidosis also increases the expression of several endoplasmic reticulum (ER) stress genes such as CHOP and ATF3. In the current study, we have thoroughly examined acidosis/GPR4-induced ER stress pathways in human umbilical vein endothelial cells (HUVEC). All three arms of the ER stress/unfolded protein response (UPR) pathways are activated by acidosis in HUVEC, as we observed an increased expression of phosphorylated eIF2α, phosphorylated IRE1α, and cleaved ATF6 upon acidic pH treatment. In addition, the expression of other downstream mediators of the UPR, such as ATF4, ATF3, CHOP and spliced XBP1, were also induced by acidosis at the mRNA and/or protein levels. Through genetic modifications and a small molecule inhibitor to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis stimulation. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in endothelial cells may regulate angiogenesis and inflammatory response in the acidic tumor microenvironment. Citation Format: Lixue Dong, Elizabeth A. Krewson, Li V. Yang. Acidic microenvironment activates endoplasmic reticulum stress pathways through GPR4 in human vascular endothelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3200. doi:10.1158/1538-7445.AM2015-3200