bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020–02–09
nine papers selected by
Susan Logue, University of Manitoba
  1. The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias.
  2. Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.
  3. Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart.
  4. Dynamics and clustering of IRE1α during ER stress.
  5. Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss.
  6. Highlighting Curcumin-Induced Crosstalk between Autophagy and Apoptosis as Supported by Its Specific Subcellular Localization.
  7. Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle.
  8. Impaired lipid metabolism by age-dependent DNA methylation alterations accelerates aging.
  9. Blockade of HSP70 by VER-155008 synergistically enhances bortezomib-induced cytotoxicity in multiple myeloma.
  1. Cancers (Basel). 2020 Feb 01. pii: E333. [Epub ahead of print]12(2):
    The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias.
    Alberto M Martelli, Francesca Paganelli, Francesca Chiarini, Camilla Evangelisti, James A McCubrey.
      The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.
    Keywords:  apoptosis; genetic anomalies; prognosis; survival; targeted therapy
    DOI:  https://doi.org/10.3390/cancers12020333
  2. Sci Rep. 2020 Feb 07. 10(1): 2160
    Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.
    Soma Samanta, Shuzo Tamura, Louis Dubeau, Paulette Mhawech-Fauceglia, Yohei Miyagi, Hisamori Kato, Rich Lieberman, Ronald J Buckanovich, Yvonne G Lin, Nouri Neamati.
      Epithelial ovarian cancer (EOC) is a leading cause of cancer-related mortality in the United States due to the late-stage disease at diagnosis. Overexpression of GRP78 and PDI following endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) promote growth and invasion in cancer. To identify novel prognostic biomarkers in EOC, here we determined the expression of ER stress-associated proteins (GRP78, ATF6 and PERK) and correlated with clinical outcome in EOC. Tissue microarray (TMA) samples from 415 tissues collected from three cancer centers (UM, USC, and KCCRI) were used to assess the expression levels of ER-associated proteins using immunohistochemistry (IHC). We observed that the expression levels of GRP78 (p < 0.0001), ATF6 (p < 0.0001), and PERK (p < 0.0001) were significantly increased in specimens of EOC compared to normal tissues, including in the serous subtype (p < 0.0001). Previously we reported that high expression of PDI correlated with poor patient survival in EOC. Here we showed that overexpression of GRP78 and PDI protein expression correlated with poor patient survival (p = 0.03), while low expression of combined GRP78 and PDI correlated with better survival (p = 0.01) in high-grade serous. The increased expression of ER stress-associated proteins in EOC suggests a role for ER stress and the UPR in EOC. More importantly, our results demonstrate that GRP78 and PDI are potential biomarkers for EOC and could be used as dual prognostic markers.
    DOI:  https://doi.org/10.1038/s41598-020-59116-x
  3. Front Cardiovasc Med. 2019 ;6 193
    Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart.
    Adrian Arrieta, Erik A Blackwood, Winston T Stauffer, Christopher C Glembotski.
      The integrity of the proteome in cardiac myocytes is critical for robust heart function. Proteome integrity in all cells is managed by protein homeostasis or proteostasis, which encompasses processes that maintain the balance of protein synthesis, folding, and degradation in ways that allow cells to adapt to conditions that present a potential challenge to viability (1). While there are processes in various cellular locations in cardiac myocytes that contribute to proteostasis, those in the cytosol, mitochondria and endoplasmic reticulum (ER) have dominant roles in maintaining cardiac contractile function. Cytosolic proteostasis has been reviewed elsewhere (2, 3); accordingly, this review focuses on proteostasis in the ER and mitochondria, and how they might influence each other and, thus, impact heart function in the settings of cardiac physiology and disease.
    Keywords:  UPR; endoplasmic reticulum; mitochondria; protein folding; proteostasis
    DOI:  https://doi.org/10.3389/fcvm.2019.00193
  4. Proc Natl Acad Sci U S A. 2020 Feb 04. pii: 201921799. [Epub ahead of print]
    Dynamics and clustering of IRE1α during ER stress.
    T Kelly Rainbolt, Judith Frydman.
      
    DOI:  https://doi.org/10.1073/pnas.1921799117
  5. Cell Death Dis. 2020 Feb 06. 11(2): 100
    Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss.
    Anni Herranen, Kuu Ikäheimo, Tuuli Lankinen, Emmi Pakarinen, Bernd Fritzsch, Mart Saarma, Maria Lindahl, Ulla Pirvola.
      The non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf-inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf-inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf-inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.
    DOI:  https://doi.org/10.1038/s41419-020-2286-6
  6. Cells. 2020 Feb 04. pii: E361. [Epub ahead of print]9(2):
    Highlighting Curcumin-Induced Crosstalk between Autophagy and Apoptosis as Supported by Its Specific Subcellular Localization.
    Francisco J Sala de Oyanguren, Nathan E Rainey, Aoula Moustapha, Ana Saric, Franck Sureau, José-Enrique O'Connor, Patrice X Petit.
      Curcumin, a major active component of turmeric (Curcuma longa, L.), is known to have various effects on both healthy and cancerous tissues. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying the anticancer effect of curcumin is still unclear. Since there is a recent consensus about endoplasmic reticulum (ER) stress being involved in the cytotoxicity of natural compounds, we have investigated using Image flow cytometry the mechanistic aspects of curcumin's destabilization of the ER, but also the status of the lysosomal compartment. Curcumin induces ER stress, thereby causing an unfolded protein response and calcium release, which destabilizes the mitochondrial compartment and induce apoptosis. These events are also associated with secondary lysosomal membrane permeabilization that occurs later together with an activation of caspase-8, mediated by cathepsins and calpains that ended in the disruption of mitochondrial homeostasis. These two pathways of different intensities and momentum converge towards an amplification of cell death. In the present study, curcumin-induced autophagy failed to rescue all cells that underwent type II cell death following initial autophagic processes. However, a small number of cells were rescued (successful autophagy) to give rise to a novel proliferation phase.
    Keywords:  ROS; apoptosis; autophagy; calcium; cancer; cell death; endoplasmic reticulum; lysosome; real-time cellular impedance; xCELLigence
    DOI:  https://doi.org/10.3390/cells9020361
  7. Front Cell Dev Biol. 2019 ;7 374
    Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle.
    Philippe Delmotte, Gary C Sieck.
      Inflammatory airway diseases such as asthma affect more than 300 million people world-wide. Inflammation triggers pathophysiology via such as tumor necrosis factor α (TNFα) and interleukins (e.g., IL-13). Hypercontraction of airway smooth muscle (ASM) and ASM cell proliferation are major contributors to the exaggerated airway narrowing that occurs during agonist stimulation. An emergent theme in this context is the role of inflammation-induced endoplasmic reticulum (ER) stress and altered mitochondrial function including an increase in the formation of reactive oxygen species (ROS). This may establish a vicious cycle as excess ROS generation leads to further ER stress. Yet, it is unclear whether inflammation-induced ROS is the major mechanism leading to ER stress or the consequence of ER stress. In various diseases, inflammation leads to an increase in mitochondrial fission (fragmentation), associated with reduced levels of mitochondrial fusion proteins, such as mitofusin 2 (Mfn2). Mitochondrial fragmentation may be a homeostatic response since it is generally coupled with mitochondrial biogenesis and mitochondrial volume density thereby reducing demand on individual mitochondrion. ER stress is triggered by the accumulation of unfolded proteins, which induces a homeostatic response to alter protein balance via effects on protein synthesis and degradation. In addition, the ER stress response promotes protein folding via increased expression of molecular chaperone proteins. Reduced Mfn2 and altered mitochondrial dynamics may not only be downstream to ER stress but also upstream such that a reduction in Mfn2 triggers further ER stress. In this review, we summarize the current understanding of the link between inflammation-induced ER stress and mitochondrial function and the role played in the pathophysiology of inflammatory airway diseases.
    Keywords:  IRE1; XBP1; asthma; inflammation; mitofusin
    DOI:  https://doi.org/10.3389/fcell.2019.00374
  8. Proc Natl Acad Sci U S A. 2020 Feb 06. pii: 201919403. [Epub ahead of print]
    Impaired lipid metabolism by age-dependent DNA methylation alterations accelerates aging.
    Xin Li, Jiaqiang Wang, Leyun Wang, Guihai Feng, Gen Li, Meixin Yu, Yufei Li, Chao Liu, Xuewei Yuan, Guangxi Zang, Zhihuan Li, Ling Zhao, Hong Ouyang, Qingli Quan, Guangyu Wang, Charlotte Zhang, Oulan Li, Junkai Xiang, Jian-Kang Zhu, Wei Li, Qi Zhou, Kang Zhang.
      Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key accelerated aging phenotypes. Restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells. We revealed an epigenetic-metabolism axis contributing to aging and potentially to antiaging therapy.
    Keywords:  ER stress; aging; epigenetic alteration; lipid metabolism; mitochondrial dysfunction
    DOI:  https://doi.org/10.1073/pnas.1919403117
  9. Cell Stress Chaperones. 2020 Feb 06.
    Blockade of HSP70 by VER-155008 synergistically enhances bortezomib-induced cytotoxicity in multiple myeloma.
    Lingjuan Huang, Yanmeng Wang, Ju Bai, Yun Yang, Fangxia Wang, Yuandong Feng, Ru Zhang, Fangmei Li, Peihua Zhang, Nan Lv, Lei Lei, Jinsong Hu, Aili He.
      Proteasome inhibitor bortezomib is one of the most effective drugs currently available for the treatment of multiple myeloma (MM). However, the intrinsic and acquired resistance to bortezomib can limit its effectiveness. The activation of heat shock response has been characterized as a potential resistance mechanism protecting MM cells from bortezomib-induced cell death. In this study, in response to bortezomib therapy, we discovered that HSP70 is one of the most substantially upregulated heat shock proteins. In order to further explore approaches to sensitizing bortezomib-based treatment for MM, we investigated whether targeting HSP70 using a specific inhibitor VER-155008 combined with bortezomib could overcome the acquired resistance in MM. We found that HSP70 inhibitor VER-155008 alone significantly decreased MM cell viability. Moreover, the combination of VER-155008 and bortezomib synergistically induced MM cell apoptosis markedly in vitro. Notably, the combined treatment was found to increase the cleavage of PARP, an early marker of chemotherapy-induced apoptosis. Importantly, the reduction of anti-apoptotic Bcl-2 family member Bcl-2, Bcl-xL, and Mcl-1 and the induction of pro-apoptotic Bcl-2 family member BH3-only protein NOXA and Bim were confirmed to be tightly associated with the synergism. Finally, the ER stress marker CHOP (CCAAT-enhancer binding protein homologous protein), which can cause transcriptional activation of genes involved in cell apoptosis, was markedly induced by both VER-155008 and bortezomib. Taken together, our finding of a strong synergistic interaction between VER-155008 and bortezomib may support for combination therapy in MM patients in the future.
    Keywords:  Apoptosis; Bortezomib; HSP70; Multiple myeloma; Synergism; VER-155008
    DOI:  https://doi.org/10.1007/s12192-020-01078-0
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