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 neuro-degeneration. Upon facing ER stress, cells initially try to restore normal function by activating a conserved signaling pathway called the Unfolded Protein Response (UPR). However, if the stress is overwhelming and cells are not able to recover within a reasonable time frame, 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 high levels of ER stress due to their high rates of glucose metabolism and hypoxic conditions resulting in accumulation of under-glycosylated mis-folded proteins in the ER. The ability of cancer cells to adapt to high levels of ER stress and continue to survive has been correlated to their invasiveness/malignancy and chemo-resistance. Thus, to be able to design effective molecularly targeted therapeutic strategies, it is crucial to delineate the signaling mechanisms that endow cancer cells with a cyto-protective phenotype. In this proposal we aim to identify important proteins that play a decisive role in promoting cancer cell survival through ER stress. We will focus on a signaling protein called G?-interacting vesicle associated protein (GIV), which has been shown to be overexpressed and to promote survival and migratory signals in many types of cancer. Based on our preliminary data and other published work in the field, we hypothesize that GIV plays a crucial role in promotion of cyto- protective signals in cancer cells experiencing ER stress. To test our hypothesis, we will use a multitude of cutting-edge sophisticated biochemical, cellular, proteomic and molecular techniques to: (1) investigate the survival signals that GIV promotes during ER stress (2) identify and characterize ER-stress dependent protein-protein interactions mediated by GIV and generate a phospho-profile of GIV to understand the mechanism by which GIV gets activated 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, and chemo-resistance. 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. In addition, our findings will also potentially shed light on molecular dissimilarities between the cellular response of cancer cells and that of the other diseases whose etiology involves ER stress-induced cell death.

Public Health Relevance

According to the World Health Organization, cancer is one of the leading causes of mortality worldwide, with more than 8 million deaths annually. One of the major hurdles in designing effective chemotherapy and molecularly targeted therapies is the ability of cancer cells to survive under adverse conditions and acquisition of drug-resistance. Our proposal aims to study the role of a protein called G?-interacting vesicle associated protein in promoting cancer cell survival during chemically induced stress. Our studies will help provide knowledge of mechanism(s) by which cancer cells overcome stress and acquire drug-resistance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Pilot Research Project (SC2)
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Special Emphasis Panel (ZGM1)
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Reddy, Michael K
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California State University Long Beach
Schools of Arts and Sciences
Long Beach
United States
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Nguyen, Peter; Calderon, Rosanna; Rodriguez-Ledezma, Yoanna et al. (2018) GIV/Girdin promotes cell survival during endoplasmic reticulum stress. Mol Cell Biochem :
Roach, Brett Lee; Ngo, Jordan Matthew; Limso, Clariss et al. (2018) Identification and characterization of a novel phosphoregulatory site on cyclin-dependent kinase 5. Biochem Biophys Res Commun 504:753-758