ReviewER proteostasis addiction in cancer biology: Novel concepts
Introduction
The homeostasis of a cell is constantly challenged by fluctuations in the environment, which is dramatically altered in the context of a growing tumor. Hypoxia and low nutrient supply are two initial stress conditions that cancer cells face, which has a negative impact on several cellular processes including protein homeostasis (referred to as proteostasis [1]), a network of interconnected quality-control processes in the cell that maintains the functional proteome. The endoplasmic reticulum (ER) is the main subcellular compartment involved in protein folding and secretion, responsible for the synthesis of at least one third of the total proteome. A complex network of chaperones, foldases, cofactors, quality control mechanisms and processing enzymes assist the correct folding of proteins at the ER that, together with an optimal intraluminal environment (i.e. redox state and calcium concentrations), ensure an efficient production of proteins [2]. Different physiological and pathological perturbations can alter global proteostasis reflected on an abnormal accumulation of misfolded proteins, which also represents an emerging topic in the cancer field. ER stress triggers an adaptive mechanism to cope with protein misfolding known as the unfolded protein response (UPR) [3]. Importantly, abnormal ER proteostasis has been extensively linked to several human diseases including neurodegeneration, stroke, diabetes, autoimmunity, among other diseases [4], [5]. In the last years, components of the proteostasis network are emerging as relevant therapeutic targets to trigger the regression of tumor development [1], [6]. The UPR contributes cancer and tumor growth [7], [8] and recent drug discovery efforts have uncovered the potential of targeting UPR components to treat cancer [9], [10].
In tumor cells, ER stress is triggered in part by different micro environmental alterations such as hypoxia, nutrient deprivation and acidosis [11]. This stressful microenvironment activates the UPR, acting as a selective factor to promote adaptation to stress and cell survival in cancer cells, increasing aggressiveness and resistance to certain chemotherapeutic agents [8], [12]. The participation of the UPR to tumor growth is well defined and supported by multiple studies in preclinical models of cancer (reviewed in [13], [14]). Importantly, new concepts are emerging in the field due to the discovery of unanticipated roles of ER stress signaling in other aspects of cancer biology, including oncogenic transformation, angiogenesis, genomic instability, metastasis and immunomodulation [8]. In this article we overview recent advances on our understanding of how the UPR contributes to cancer development beyond its role as a survival factor to the hypoxic conditions in solid tumors. The possible therapeutic implications of targeting the UPR on a disease context are also highlighted.
Section snippets
ER stress signaling pathways
The UPR is initiated by at least three types of stress sensors located at the ER membrane, known as PKR-like ER kinase (PERK), Inositol-requiring enzyme 1 (IRE1) and Activating transcription factor 6 (ATF6) [3]. Each of these sensors transduces information about the intensity and duration of the stress stimuli to the cytosol and the nucleus either to adjust proteostasis or induce apoptosis of irreversible damaged cells. Thus the UPR is a central controller of cell fate under ER stress. Upon
The UPR in tumorigenesis: hypoxia, cell survival and oncogenic transformation.
Cancer development involves a rapid growth of tumors that requires nutrient supply and oxygen consumption that eventually exceeds the capacity of the existing vascular structures resulting in microenvironmental stress. Although most tumors become hypoxic and nutrient depleted, induction of ER stress has been shown to contribute to local angiogenesis and cell survival under these conditions. In this section, we briefly discuss the well-known role of the UPR in supporting tumor growth.
Hypoxia is
Non-conventional links between the UPR and cancer
Most of the studies in the field have associated the activity of the UPR with the survival of cells in solid tumors, providing selective advantages that contribute to cancer progression. In this section, we discuss recent discoveries highlighting novel molecular aspects linking ER stress signaling with angiogenesis, genomic instability, metastasis and the modulation of immune responses.
Perspective
Significant progress has been made in the field to elucidate the contribution of the UPR to oncogenesis and cancer. Several recent drug screenings have identified interesting compounds to target selective UPR components with potent anticancer efficacy [9]. Most of the studies in the field are focused in defining the impact of ER stress to the adaptive capacity of cancer cells and survive to the adverse conditions of the tumor microenvironment. The UPR is part of the mechanism generating
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
We thank Denisse Sepulveda to collaborate on this review. This work was funded by FONDECYT No. 1140549, Ring Initiative ACT1109, FONDEF D11I1007, Millennium Institute No. P09-015-F, the Frick Foundation, Michael J Fox Foundation for Parkinson Research, COPEC-UC Foundation, CONICYT grant USA2013-0003, and ECOS-CONICYT C13S02 (CH). ED and HU are doctoral fellows supported by a CONICYT fellowship and by a CONICYT research grant.
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