Molecular Mechanisms Underlying Cell Survival During Endoplasmic Reticulum Stress

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ABSTRACT Endoplasmic reticulum (ER) stress is a form of cellular stress that is experienced by our cells both under normal physiological conditions such as in professional secretory cells and disease states such as cancer, diabetes and neurodegeneration. Upon facing ER stress, cells initially attempt to restore normal function by activating a conserved signaling pathway called the unfolded protein response (UPR). However, if the stress becomes chronic and homeostasis is not restored within a reasonable timeframe, the UPR ultimately commits cells to programmed cell death. How cells make this life-or-death decision remains an exciting yet poorly understood phenomenon. Cancer cells exhibit ER stress due to their high rates of glucose metabolism and hypoxic conditions resulting in accumulation of underglycosylated, misfolded proteins in the ER. The ability of cancer cells to successfully adapt to ER stress and continue to survive has been correlated to their invasiveness/malignancy and chemoresistance. Thus, to be able to design effective molecularly targeted therapeutic strategies, it is crucial to delineate the mechanisms that endow cancer cells with cytoprotection in the face of ER stress. The main objective of this proposal is to investigate the molecular mechanisms that play a decisive role in promoting cell survival through ER stress. With the central hypothesis that the pro-survival Akt pathway regulates the UPR to determine the overall cell fate, we will (A) Aim 1: investigate the role of Akt in regulation of signals originating from the UPR sensors in response to stress (B) Aim 2: determine the mechanism by which Akt is activated in a non-canonical manner during ER stress. Our results will potentially lead to important revelations as to how cancer cells gain a cytoprotective advantage during ER stress resulting in prolonged survival. The successful completion of our proposal will advance the field in terms of enhancing our fundamental knowledge of a fascinating cell biological process as well as finding new and key targets for curbing cancer cell survival.