Effect of inhibition of the PI3K‐Akt pathway on the Unfolded Protein Response

Abstract

The endoplasmic reticulum (ER) is an organelle in eukaryotic cells that plays a vital role in many important cellular functions including proper folding of secretory and membrane proteins. Any disruption of ER function triggers ER stress leading to activation of an evolutionarily conserved signaling program called the Unfolded Protein Response (UPR). UPR signaling initially aids in re‐establishing normal ER functions and promotes cell viability. However, if the homeostasis is not restored in a timely manner, UPR eventually commits the cells to death. Cancer cells are known to be able to evade ER stress‐induced cell death, which helps them acquire resistance to therapy. Our laboratory has previously shown that Protein kinase B aka Akt is activated in ER stressed cancer cells leading to enhanced cell survival. The goal of this project was to test if Akt activation modulates the outcome of UPR signaling. We treated cells with commercially available inhibitors of the PI3K‐Akt pathway and analyzed changes in the expression and/or post‐translational modification of known UPR signaling proteins by immunoblotting. Our data show that the PI3K‐Akt pathway inactivation differentially regulates the outcome of UPR signaling. Our current experiments are focused on studying the effect of PI3K‐Akt inhibition on viability of multiple cancer cell lines exposed to ER stress.Support or Funding InformationThis project is supported by the NIGMS‐NIH grant #SC2GM121246.