Abstract SY44-03: Targeting the unfolded protein response in cancer
Authors: Wang Miao , Kaufman Randal J. 
Published: May 2015

The endoplasmic reticulum (ER) is an essential organelle for all eukaryotic cells that evolved for calcium storage and signaling and as the entrance to the secretory pathway, for which 1/3 of all cellular proteins traffic to ensure intracellular and extracellular homeostasis. Numerous environmental, physiological and pathological insults, as well as nutrient fluctuations can disrupt the protein-folding environment of the ER to cause protein misfolding and accumulation of misfolded proteins, referred to as ER stress which triggers the activation of the unfolded protein response (UPR) to restore ER homeostasis. The UPR comprises three sensors that initiate signaling: PKR-related ER kinase (PERK), inositol requiring enxyme-1α (IRE1α) and activating transcription factor 6α (ATF6α). Under non-stressed conditions, binding of the ER luminal protein chaperone BIP to all three sensors prevents their signaling. Upon conditions that cause ER stress, BIP binds to misfolded proteins as they accumulate in the ER, thereby promoting release from the sensors to permit their signaling. PERK released from BIP forms homodimers for transautophosphorylation and activation of the kinase activity. Activated PERK phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), leading to attenuation of mRNA translation.

In a similar manner, BIP release causes IRE1α homodimerization and trans-autophosphorylation to activate its endoribonuclease function to initiate unconventional splicing of a 26 base intron within the X-box binding protein-1 (Xbp1) mRNA, thereby generating a translational frame-shift to produce a potent transcriptional activator. In contrast, BIP release from ATF6α permits trafficking of ATF6α to the cis-Golgi compartment where it is processed by site-1 and site-2 proteases to release a cytosolic fragment that migrates to the nucleus to activation transcription of target genes. Therefore, the outcome of UPR activation involves transient inhibition of protein synthesis mediated by PERK-eIF2α, whereas the IRE1α-Xbp1 and ATF6α pathways generate transcription factors to activate genes encoding primarily adaptive functions that increase the capacity for ER protein translocation, folding and transport and processes that eliminate misfolded proteins, ER-associated protein degradation (ERAD) and autophagy. If the UPR cannot resolve the protein-folding defect, the UPR is intrinsically wired to initiate apoptosis. It is now evident that ER stress and UPR activation contribute to the pathology of many, if not all, degenerative diseases.

Rapidly accumulating data demonstrate that ER stress and UPR activation occurs in many human cancer types, which parallels resistance to cancer therapies and poor prognosis. The crosstalk between the UPR pathways and master metabolic mediators essential for cancer development and progression has demonstrated a connection between UPR activation and cancer progression. Protein folding and processing in the ER and transport to other organelles occurs as a series of complex energy-consuming reactions. As a result, proper ER function is highly susceptible to energy fluctuations in the cell and may serve as a sensor for nutrient availability and cell metabolic status. As expected, conditions of low nutrient supply (e.g., glucose deprivation or hypoxia at poorly vascularized tumor beds) induce ER stress and activation of the UPR that, besides its remedial function in protein maturation and transport, protects from cell death and restores energy homeostasis. On the other hand, excess nutrients (fatty acids, cholesterol and glucose) can cause ER stress and UPR activation. This evolving concept underlying the integration of the UPR with cell metabolism is of special interest and importance in the field of cancer biology as: 1) tumor cells manifest both ER stress/UPR hyperactivation and nutrient shortage likely caused by hypoxia, nutrient deprivation and rapid cell proliferation; 2) tumors arise from nutrientrich environments at higher rates and display more malignant phenotypes.

Given that cancer usually arises and progresses in a stressful microenvironment, transformed cells may require the UPR for survival. In fact, many studies demonstrate essential roles for UPR signaling to promote tumor growth and increased UPR signaling is associated with chemoresistance. However, it was only recently that efforts provided in situ validation of UPR activation as a vital step during oncogenic transformation and cancer development. These studies suggest that UPR signaling molecules interact with well-established oncogene / tumor suppressor gene networks to modulate their function in cancer development. For example, PERK-dependent UPR activation promotes c-Myc-induced cell transformation through autophagy; and loss of PTEN induces ER stress and results in increased aerobic glycolysis, known as the Warburg effect. UPR activation also negatively regulates some tumor suppressor genes, including p53 and TSC1/TSC2, to promote cell survival and oncogenic transformation. In other cases, sustained UPR activation in response to prolonged ER stress leads to cell death or senescence in pre-malignant cells to prevent neoplastic progression. Therefore, it seems that the premalignant cells utilize UPR activation as a survival tool if the gene mutations in premalignant cells can overcome or bypass the UPR activation-dependent cell apoptosis or senescence. It will be of significant importance to understand exactly how these signaling pathways regulate each other, their interdependence and how interference of one alters signaling through other pathways. Furthermore, ER stress and UPR activation also play a tumor supportive role in the tumor microenvironment through stimulating angiogenesis and compromising host immune surveillance.

Aside from its pro-survival role, prolonged UPR activation due to severe and unresolved ER stress leads to cell death. This greatly complicates the development of drugs targeted to inhibit the UPR for cancer treatment, which target not only cancer cells, but also the tumor microenvironment. Indeed, bortezomib was the first proteasome inhibitor approved by the U.S. FDA for cancer therapy as a consequence of success in treating multiple myeloma and mantle cell lymphoma. However, since UPR activation can function as a double-edged sword by supporting or repressing cancer initiation and/or progression, caution is necessary in designing therapies that target the UPR components and interpretation of data from these studies. Meanwhile, ER stress and UPR activation may alter the cancer cell response to other chemotherapeutic agents, offering an attractive approach target for combined therapy.

One of the most major concerns of inhibiting the UPR in cancer therapy is the selectivity of the agent. Many cell types require efficient UPR signaling for their function, most notably pancreatic beta cells and plasma cells. However, there might exist opportunities for anti-UPR therapies, since the UPR is only important for survival of cells in a stressful environment. Due to the unique harsh growth conditions that tumor cells encounter, they might be predisposed to cell death upon selective inhibition of UPR pathways.

Citation Format: Miao Wang, Randal J. Kaufman. Targeting the unfolded protein response in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY44-03. doi:10.1158/1538-7445.AM2014-SY44-03