The unfolded protein response signaling drives prostate cancer

Precise control of cell signaling is essential of normal physiology and health, whereas its abnormalities result in pathological conditions. In cancer, a variety of signaling pathways are deregulated and drive cancer progression. Consistently, a large number of the drugs that are currently used in the clinic target cell signaling. The goal of this project is to identify, validate, and target key signaling events in prostate cancer (PCa) in order to develop novel biomarkers and therapies. In particular, we focus on the unfolded protein response (UPR) signaling pathways that we have recently found to be regulated by androgen signaling, a pathway that is implicated in all phases of PCa and is currently the target of main therapies in the clinic. Recently published and yet unpublished work from our laboratory has identified UPR to be of central importance for PCa growth and survival in preclinical models. The goal of this project is to identify the molecular details of these stress signaling networks and use this information for biomarker discovery and novel therapeutic approaches for PCa. To achieve this goal, we use advanced nanoparticle chemistry, biochemical, molecular, cell biological, genetic, and translational studies, as well as analysis of novel clinical cohorts, coupled to innovative and comprehensive computational methods. Since the commencement of the project, we have made significant progress on various fronts. First, we have characterized the molecular mechanisms through which one of three canonical arms of UPR, PERK-eIF2a-ATF4, contributes to PCa growth and survival. We have found that one of the ATF4 target genes is MTHFD2, that encodes an enzyme in a central metabolic pathway in the mitochondria, and that it is essential for PCa in models in vitro and in vivo. Our findings suggest that MTHFD2 may be a therapeutic target for PCa. We are evaluating this possibility by further in vivo experimentation and nanoparticle-mediated knockdown.Second, we have identified additional novel targets of ATF4 that we are currently functionally characterizing. At least one of them appear to be also required for PCa growth and survival indicating the important role of PERK-eIF2a-ATF4 signaling to PCa. Third, we have established cell lines and characterized them to study different arms of the UPR in a high-throughput manner. Fourth, we have found that there are coordinate effects of UPR pathways on PCa growth and survival. These studies are helping to dissect the details of UPR signaling as they relate to PCa and may also have general mechanistic consequences.

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Cell signaling is at the heart of normal physiology and health, whereas its perturbations are key to pathological conditions. In cancer, a variety of signaling pathways are deregulated and drive cancer progression. Consistently, a large number of the drugs that are currently used in the clinic target cell signaling. The goal of this project is to identify, validate, and target key signaling events in prostate cancer (PCa) in order to develop novel biomarkers and therapies. In particular, we focus on the unfolded stress response (UPR) signaling pathways that are regulated by androgen signaling, a pathway that is implicated in all phases of PCa and is currently the target of main therapies in the clinic. Even though primary target gene program of androgen signaling has been reported in different settings, functional characterization has been limited and it is not clear which one(s) of these are most important for PCa growth and survival. Recently published and yet unpublished work from our laboratory has identified unfolded stress signaling to be of central importance for PCa growth and survival ln preclinical models. In particular, our efforts will concentrate on the IRE1-XBP1 and PERK-eIF2a arms of the UPR, their crosstalk with each other and with other signaling pathways in the PCa cell. The goal of this project is to identify the molecular details of these stress signaling networks and use this information for biomarker discovery and novel therapeutic approaches for PCa. To achieve this goal, we use advanced nanoparticle chemistry, biochemical, molecular, cell biological, genetic, and translational studies, as well as analysis of novel clinical cohorts, coupled to innovative and comprehensive computational methods.