bims-unfpre Biomed news
on Unfolded protein response
Issue of 2019‒01‒20
seven papers selected by
Susan Logue
Apoptosis Research Centre


  1. Nat Commun. 2019 Jan 14. 10(1): 187
    Blackwood EA, Azizi K, Thuerauf DJ, Paxman RJ, Plate L, Kelly JW, Wiseman RL, Glembotski CC.
      Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.
    DOI:  https://doi.org/10.1038/s41467-018-08129-2
  2. Cancer Immunol Res. 2019 Jan 18. pii: canimm.0182.2018. [Epub ahead of print]
    Hurst K, Lawrence KA, Essman MT, Walton ZJ, Leddy LR, Thaxton JE.
      Tumor antigen-specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which energy loss and inhibition of effector function occur in tumor infiltrating lymphocytes (TILs) are ill-defined, and methods to identify tumor-antigen-specific TILs that experience such stress are unknown. Processes upstream of the mitochondria guide cell-intrinsic energy depletion. We hypothesized that a mechanism of T cell-intrinsic energy consumption was the process of oxidative protein folding and disulfide-bond formation that takes place in the endoplasmic reticulum (ER) guided by protein kinase R-like endoplasmic reticulum kinase (PERK) and downstream PERK axis target ER oxidoreductase 1 (ERO1α). To test this hypothesis, we created TCR transgenic mice with a T cell-specific PERK gene deletion (OT1+Lckcre+PERKf/f, PERK KO). We found that PERK KO and T cells that were pharmacologically inhibited by PERK or ERO1α maintained reserve energy and exhibited a protein profile consistent with reduced oxidative stress. These T cell groups displayed superior tumor control compared to T effectors. We identified a biomarker of ER-induced mitochondrial exhaustion in T cells as mitochondrial reactive oxygen species (mtROS), and found that PD-1+ tumor antigen-specific CD8+ TILs express mtROS. In vivo treatment with a PERK inhibitor abrogated mtROS in PD-1+ CD8+ TILs and bolstered CD8+ TIL viability. Combination therapy enabled 100% survival and 71% tumor clearance in a sarcoma mouse model. Our data identify the ER as a regulator of T cell energetics and indicate that ER elements are effective targets to improve cancer immunotherapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-18-0182
  3. Elife. 2019 Jan 15. pii: e41792. [Epub ahead of print]8
    Gao K, Li Y, Hu S, Liu Y.
      Animals respond to mitochondrial stress with the induction of mitochondrial unfolded protein response (UPRmt). A cascade of events occurs upon UPRmt activation, ultimately triggering a transcriptional response governed by two transcription factors: DVE-1 and ATFS-1. Here we identify SUMO-specific peptidase ULP-4 as a positive regulator of C. elegans UPRmt to control SUMOylation status of DVE-1 and ATFS-1. SUMOylation affects these two axes in the transcriptional program of UPRmt with distinct mechanisms: change of DVE-1 subcellular localization vs. change of ATFS-1 stability and activity. Our findings reveal a post-translational modification that promotes immune response and lifespan extension during mitochondrial stress.
    Keywords:  C. elegans; cell biology
    DOI:  https://doi.org/10.7554/eLife.41792
  4. Mol Cancer Res. 2019 Jan 17. pii: molcanres.0481.2018. [Epub ahead of print]
    Sengupta S, Sevigny CM, Bhattacharya P, Jordan VC, Clarke R.
      Approximately thirty percent of aromatase-inhibitor resistant, estrogen receptor positive breast cancer patients benefit from treatment with estrogen. This enigmatic estrogen action is not well understood and how it occurs remains elusive. Studies indicate that the unfolded protein response and apoptosis pathways play important roles in mediating estrogen-triggered apoptosis. Using MCF7:5C cells, which mimic aromatase inhibitor resistance, and are hypersensitive to estrogen as evident by induction of apoptosis, we define increased global protein translational load as the trigger for estrogen-induced apoptosis. The protein kinase-RNA-like endoplasmic reticulum kinase pathway was activated followed by increased phosphorylation of eukaryotic initiation factor-2 alpha (eIF2α). These actions block global protein translation but preferentially allow high expression of specific transcription factors, such as activating transcription factor 4 and C/EBP homologous protein that facilitate apoptosis. Notably, we recapitulated this phenotype of MCF7:5C in two other endocrine therapy resistant cell lines (MCF7/LCC9 and T47D:A18/4-OHT) by increasing the levels of phospho-eIF2α using salubrinal to pharmacologically inhibit the enzymes responsible for dephosphorylation of eIF2α, GADD34, and CReP. RNAi mediated ablation of these genes induced apoptosis that used the same signaling as salubrinal treatment. Moreover, combining 4-hydroxytamoxifen with salubrinal enhanced apoptotic potency. Implications: These results not only elucidate the mechanism of estrogen-induced apoptosis but also identify a druggable target for potential therapeutic intervention that can mimic the beneficial effect of estrogen in some breast cancers.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-18-0481
  5. Oncol Lett. 2019 Jan;17(1): 660-667
    Dai L, He G, Zhang K, Guan X, Wang Y, Zhang B.
      Trichostatin A (TSA) has been demonstrated to exhibit various anticancer effects that influence cell cycle arrest, cell proliferation and apoptosis of cancer cells. A potential association between TSA and endoplasmic reticulum (ER) function has been suggested but its anticancer mechanism involving the induction of ER stress is unknown. p53 has previously been demonstrated to regulate ER function in response to stress but its role involving TSA and ER stress in cancer cells is poorly understood. The current study identified that TSA induced ER stress in wild type (WT) HCT116 human colon cancer cells. Following TSA treatment, the ER stress markers GRP78 and GRP94 significantly increased without hyperacetylation of their promoter regions. The inositol-requiring enzyme 1 α (IRE1α)/X-box binding protein 1 (XBP1) pathway was implicated due to an association of phosphorylated IRE1α and spliced XBP1 with ER stress. However, luciferase reporter assay indicated that splicing events were attenuated in HCT116 TP53(-/-) cells. Furthermore, cell viability and apoptosis were revealed to depend on p53 during TSA treatment. Cell viability increased and the apoptosis rate decreased in HCT116 TP53(-/-) cells compared with WT HCT116 cells undergoing TSA treatment. In conclusion, the current study revealed that TSA may induce ER stress via a p53-dependent mechanism in colon cancer cells. This provides information that may assist the development of treatments that exploit the anticancer function of TSA.
    Keywords:  colon cancer; endoplasmic reticulum stress; p53; trichostatin A
    DOI:  https://doi.org/10.3892/ol.2018.9641
  6. J Biol Chem. 2019 Jan 18. pii: jbc.RA118.003890. [Epub ahead of print]
    Sahu PK, Tomar RS.
      Cantharidin (CTD) is a potent anticancer small molecule produced by several species of blister beetle. It has been a traditional medicine for the management of warts and tumors for many decades.CTD suppresses tumor growth by inducing apoptosis, cell cycle arrest, and DNA damage and inhibits protein phosphatase 2 phosphatase activator (PP2A) and protein phosphatase 1 (PP1). CTD also alters lipid homeostasis, cellwall integrity, endocytosis, adhesion, and invasion in yeast cells. In this study, we identified additional molecular targets of CTD using a Saccharomyces cerevisiae strain that expresses a cantharidin resistance gene (CRG1), encoding a SAM-dependent methyltransferase that methylates and inactivates CTD. We found that CTD specifically affects phosphatidylethanolamine (PE)-associated functions that can be rescued by supplementing the growth media with ethanolamine (ETA). CTD also perturbed endoplasmic reticulum (ER) homeostasis and cell wall integrity by altering the sorting of glycophosphatidylinositol (GPI)-anchored proteins. A CTD-dependent genetic interaction profile of CRG1 revealed that activity of the lipid phosphatase cell division control protein 1 (Cdc1) in GPI-anchor remodeling is the key target of CTD, independently of PP2A and PP1 activities. Furthermore, experiments with human cells further suggested that CTD functions through a conserved mechanism in higher eukaryotes. Altogether, we conclude that CTD induces cytotoxicity by targeting Cdc1activity in GPI-anchor remodeling in the ER.
    Keywords:  Cantharidin; Cdc1; ER homeostasis; ER-Golgi transport; GPI-anchor remodelling; anticancer drug; cell signaling; glycosylphosphatidylinositol (GPI anchor); lipid metabolism; phospholipid; unfolded protein response (UPR); yeast genetics
    DOI:  https://doi.org/10.1074/jbc.RA118.003890
  7. J Pathol Transl Med. 2019 Jan 16.
    Kang HJ, Seol HS, Lee SE, Suh YA, Kim J, Jang SJ, Yu E.
      Background: Development of chemotherapeutics for the treatment of advanced hepatocellular carcinoma (HCC) has been lagging. Screening of candidate therapeutic agents by using patient-derived preclinical models may facilitate drug discovery for HCC patients.Materials and Methods: Four primary cultured HCC cells from surgically resected tumor tissues and six HCC cell lines were used for high-throughput screening of 252 drugs from the Prestwick Chemical Library®. The efficacy and mechanisms of action of the candidate anti-cancer drug were analyzed via cell viability, cell cycle assays and western blotting.
    Results: Guanabenz acetate, which has been used as an antihypertensive drug, was screened as a candidate anti-cancer agent for HCC through a drug sensitivity assay by using the primary cultured HCC cells and HCC cell lines. Guanabenz acetate reduced HCC cell viability through apoptosis and autophagy. This occurred via inhibition of growth arrest and DNA damage-inducible protein 34 (GADD34), increased phosphorylation of eukaryotic initiation factor 2α (eIF2α), increased activating transcription factor 4 (ATF4), and cell cycle arrest.
    Conclusion: Guanabenz acetate induces endoplasmic reticulum stress-related cell death in HCC and may be repositioned as an anti-cancer therapeutic agent for HCC patients.
    Keywords:  Guanabenz acetate; drug repositioning; drug sensitivity; hepatocellular carcinoma; primary culture
    DOI:  https://doi.org/10.4132/jptm.2019.01.14