scholarly journals Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2864
Author(s):  
Tina Bagratuni ◽  
Dimitrios Patseas ◽  
Nefeli Mavrianou-Koutsoukou ◽  
Christine Ivy Liacos ◽  
Aimilia D. Sklirou ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Kinase Inhibitor ◽  
Protein Kinase R ◽  
Serine Threonine Kinase ◽  
Unfolded Protein ◽  
Eif2 Alpha ◽  
Protein Response ◽  
Related Proteins ◽  
Apoptotic Effects

Due to increased immunoglobulin production and uncontrolled proliferation, multiple myeloma (MM) plasma cells develop a phenotype of deregulated unfolded protein response (UPR). The eIF2-alpha kinase 3 [EIF2αK3, protein kinase R (PKR)-like ER kinase (PERK)], the third known sensor of endoplasmic reticulum (ER) stress, is a serine-threonine kinase and, like the other two UPR-related proteins, i.e., IRE1 and ATF6, it is bound to the ER membrane. MM, like other tumors showing uncontrolled protein secretion, is highly dependent to UPR for survival; thus, inhibition of PERK can be an effective strategy to suppress growth of malignant plasma cells. Here, we have used GSK2606414, an ATP-competitive potent PERK inhibitor, and found significant anti-proliferative and apoptotic effects in a panel of MM cell lines. These effects were accompanied by the downregulation of key components of the PERK pathway as well as of other UPR elements. Consistently, PERK gene expression silencing significantly increased cell death in MM cells, highlighting the importance of PERK signaling in MM biology. Moreover, GSK2606414, in combination with the proteasome inhibitor bortezomib, exerted an additive toxic effect in MM cells. Overall, our data suggest that PERK inhibition could represent a novel combinatorial therapeutic approach in MM.

scholarly journals Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection

2022 ◽  
Vol 16 (1) ◽  
pp. e0009192
Author(s):  
Michael Weingartner ◽  
Simon Stücheli ◽  
Fadi Jebbawi ◽  
Bruno Gottstein ◽  
Guido Beldi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Echinococcus Multilocularis ◽  
Molecular Mechanisms ◽  
Disease Recurrence ◽  
Unfolded Protein ◽  
Programmed Death ◽  
Protein Response ◽  
Host Parasite ◽  
Related Proteins

Background Echinococcus multilocularis causes alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to chemotherapy using benzimidazoles and surgical intervention, with frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlying E. multilocularis infections and host-parasite interactions ultimately aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection in mice. Methods E. multilocularis- and mock-infected C57BL/6 mice were subdivided into vehicle, albendazole (ABZ) and anti-programmed death ligand 1 (αPD-L1) treated groups. To mimic a chronic infection, treatments of mice started six weeks post i.p. infection and continued for another eight weeks. Liver tissue was then collected to examine inflammatory cytokines and the expression of UPR- and ERS-related genes. Results E. multilocularis infection led to an upregulation of UPR- and ERS-related proteins in the liver, including ATF6, CHOP, GRP78, ERp72, H6PD and calreticulin, whilst PERK and its target eIF2α were not affected, and IRE1α and ATF4 were downregulated. ABZ treatment in E. multilocularis infected mice reversed, or at least tended to reverse, these protein expression changes to levels seen in mock-infected mice. Furthermore, ABZ treatment reversed the elevated levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in the liver of infected mice. Similar to ABZ, αPD-L1 immune-treatment tended to reverse the increased CHOP and decreased ATF4 and IRE1α expression levels. Conclusions and significance AE caused chronic inflammation, UPR activation and ERS in mice. The E. multilocularis-induced inflammation and consecutive ERS was ameliorated by ABZ and αPD-L1 treatment, indicating their effectiveness to inhibit parasite proliferation and downregulate its activity status. Neither ABZ nor αPD-L1 themselves affected UPR in control mice. Further research is needed to elucidate the link between inflammation, UPR and ERS, and if these pathways offer potential for improved therapies of patients with AE.

scholarly journals Dysregulation in the Unfolded Protein Response in the FGR Rat Pancreas

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaomei Liu ◽  
Yanyan Guo ◽  
Jun Wang ◽  
Liangliang Zhu ◽  
Linlin Gao
Keyword(s):  
Protein Kinase ◽  
Unfolded Protein Response ◽  
Binding Protein ◽  
Protein Kinase R ◽  
Pregnant Rats ◽  
Fetal Pancreas ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition in utero on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2α were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.

The Human Plasma Cell Gene Expression Program.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3242-3242
Author(s):  
John De Vos ◽  
Dirk Hose ◽  
Thierry Reme ◽  
Hartmut Goldschmidt ◽  
Jean-Francois Rossi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
Plasma Cell ◽  
Expression Profile ◽  
Plasma Cells ◽  
Plasma Cell Differentiation ◽  
Unfolded Protein ◽  
The Mean ◽  
Protein Response

Abstract Seven purified peripheral blood memory B-cells (BM), seven in-vitro-generated polyclonal plasmablastic cells (PPC) and seven purified bone marrow mature plasma cells (BMPC) were studied by oligonucleotide microarrays. All samples were obtained from healthy volunteers. The gene expression profiling of these samples was determined with Affymetrix pan genomic U133A + B arrays (44 928 oligonucleotide probesets). We determined that 2313 genes were differentially expressed between these three B cell categories (P 〈 0.01 by a Kruskal-Wallis test and a ratio between two categories 〉 3). These 2313 genes were classified into six categories, according to the expression profile: early plasma cell genes (EPC), late plasma cell genes (LPC), genes lost early during plasma cell differentiation (LEPC), genes lost late during plasma cell differentiation (LLPC), genes upregulated only in plasmablasts (PBO) and genes lost only in plasmablasts (LPBO). As expected, Ig transcripts where essentially classified as EPC. As a corollary, genes involved in protein synthesis or degradation, transmembrane transporters and metabolism genes were overrepresented in EPC genes. Interestingly, genes involved in intercellular communication and extracellular matrix were enriched in LPC, highlighting the fact that mature plasma cells develop tight interactions with the bone marrow environment. Of note, genes involved in cell cycle are upregulated mainly in plasmablasts, whereas antiapoptotic genes are lost in plasmablasts only. Mains genes known to be involved in plasma cell differentiation display an expression profile in agreement with published data, as illustrated for transcription factors in Figure 1, validating this DNA microarray dataset. However most of these 2313 genes have either never been described yet or have no yet been linked to plasma cell differentiation. The description of those genes among our genome whose expression vary most during plasma cell differentiation will be an essential step in understanding the biology of a cell type essential to immune defenses and involved in deadly diseases. Figure 1: Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response. Figure 1:. Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response.

XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 250-253 ◽  
Author(s):  
Tina Bagratuni ◽  
Ping Wu ◽  
David Gonzalez de Castro ◽  
Emma L. Davenport ◽  
Nicholas J. Dickens ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Protein Production ◽  
Plasma Cells ◽  
Therapeutic Effects ◽  
Immunoglobulin Production ◽  
Independent Prognostic Marker ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Gene Expression Levels

Abstract Immunoglobulin production by myeloma plasma cells depends on the unfolded protein response for protein production and folding. Recent studies have highlighted the importance of IRE1α and X box binding protein 1 (XBP1), key members of this pathway, in normal B-plasma cell development. We have determined the gene expression levels of IRE1α, XBP1, XBP1UNSPLICED (XBP1u), and XBP1SPLICED (XBP1s) in a series of patients with myeloma and correlated findings with clinical outcome. We show that IRE1α and XBP1 are highly expressed and that patients with low XBP1s/u ratios have a significantly better overall survival. XBP1s is an independent prognostic marker and can be used with β2 microglobulin and t(4;14) to identify a group of patients with a poor outcome. Furthermore, we show the beneficial therapeutic effects of thalidomide in patients with low XBP1s/u ratios. This study highlights the importance of XBP1 in myeloma and its significance as an independent prognostic marker and as a predictor of thalidomide response. This trial was registered at www.controlled-trials.com/ISRCTN68454111/68454111 as #ISRCTN684541111.

scholarly journals Mfn2 Regulates High Glucose-Induced MAMs Dysfunction and Apoptosis in Podocytes via PERK Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Yun Cao ◽  
Zhaowei Chen ◽  
Jijia Hu ◽  
Jun Feng ◽  
Zijing Zhu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Diabetic Rats ◽  
Mitochondrial Morphology ◽  
Podocyte Injury ◽  
Unfolded Protein ◽  
Mitochondrial Functions ◽  
Protein Response ◽  
Apoptotic Effects

The endoplasmic reticulum (ER) stress and mitochondrial dysfunction in high glucose (HG)-induced podocyte injury have been demonstrated to the progression of diabetic kidney disease (DKD). However, the pathological mechanisms remain equivocal. Mitofusin2 (Mfn2) was initially identified as a dynamin-like protein involved in fusing the outer mitochondrial membrane (OMM). More recently, Mfn2 has been reported to be located at the ER membranes that contact OMM. Mitochondria-associated ER membranes (MAMs) is the intercellular membrane subdomain, which connects the mitochondria and ER through a proteinaceous tether. Here, we observed the suppression of Mfn2 expression in the glomeruli and glomerular podocytes of patients with DKD. Streptozotocin (STZ)-induced diabetic rats exhibited abnormal mitochondrial morphology and MAMs reduction in podocytes, accompanied by decreased expression of Mfn2 and activation of all three unfolded protein response (UPR) pathways (IRE1, ATF6, and PERK). The HG-induced mitochondrial dysfunction, MAMs reduction, and increased apoptosis in vitro were accompanied by the downregulation of Mfn2 and activation of the PERK pathway. Mfn2 physically interacts with PERK, and HG promotes a decrease in Mfn2-PERK interaction. In addition, Mfn2-silenced podocytes showed mitochondrial dysfunction, MAMs reduction, activation of PERK pathway, and increased apoptosis. Conversely, all these effects of HG stimulation were alleviated significantly by Mfn2 overexpression. Furthermore, the inhibition of PERK phosphorylation protected mitochondrial functions but did not affect the expression of Mfn2 in HG-treated podocytes. Therefore, this study confirmed that Mfn2 regulates the morphology and functions of MAMs and mitochondria, and exerts anti-apoptotic effects on podocytes by inhibiting the PERK pathway. Hence, the Mfn2-PERK signaling pathway may be a new therapeutic target for preventing podocyte injury in DKD.

scholarly journals Regulation of the ER stress response by a mitochondrial microprotein

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Qian Chu ◽  
Thomas F. Martinez ◽  
Sammy Weiser Novak ◽  
Cynthia J. Donaldson ◽  
Dan Tan ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Mitochondrial Outer Membrane ◽  
Unfolded Proteins ◽  
Functional Studies ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Organelle Communication ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER–mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an undiscovered role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.

scholarly journals Stress macht Zellen resistent gegen Folsäure-basierte Chemotherapeutika

BIOspektrum ◽  
2020 ◽  
Vol 26 (6) ◽  
pp. 609-611
Author(s):  
Robert Ahrends ◽  
Jan Medenbach
Keyword(s):  
Gene Regulation ◽  
Stress Response ◽  
Molecular Mechanisms ◽  
Cellular Stress Response ◽  
Resistance To Therapy ◽  
Unfolded Protein ◽  
Stress Response Pathway ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The unfolded protein response (UPR), a cellular stress response pathway, is broadly implicated in disease and resistance to therapy. The molecular mechanisms that drive stress-mediated chemoresistance are, however, only poorly understood. We have employed a multiomics approach to determine UPR-induced gene regulation, revealing the UPR regulon. We further observe metabolic rewiring upon stress and resistance to Methotrexate, a widely-employed therapeutic reagent. The precise molecular characterization of the pathway driving resistance might lead to novel concepts in cancer therapy.

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