bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒10‒16
eleven papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto
  1. Piperlongumine and bortezomib synergically inhibit cholangiocarcinoma via ER stress-induced cell death.
  2. Corynoxine suppresses pancreatic cancer growth primarily via ROS-p38 mediated cytostatic effects.
  3. Curcumin Enhanced Ionizing Radiation-Induced Immunogenic Cell Death in Glioma Cells through Endoplasmic Reticulum Stress Signaling Pathways.
  4. Mitoregulin controls mitochondrial function and stress-adaptation response during early phase of endoplasmic reticulum stress in breast cancer cells.
  5. Pllans-II Induces Cell Death in Cervical Cancer Squamous Epithelial Cells via Unfolded Protein Accumulation and Endoplasmic Reticulum Stress.
  6. Diterpenoid DGA induces apoptosis via endoplasmic reticulum stress caused by changes in glycosphingolipid composition and inhibition of STAT3 in glioma cells.
  7. UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis.
  8. Polo-Like Kinase 2 Plays an Essential Role in Cytoprotection against MG132-Induced Proteasome Inhibition via Phosphorylation of Serine 19 in HSPB5.
  9. Exosomal DNAJB11 promotes the development of pancreatic cancer by modulating the EGFR/MAPK pathway.
  10. IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.
  11. Corrigendum: Comprehensive analysis of the clinical and biological significances of endoplasmic reticulum stress in diffuse gliomas.
  1. Naunyn Schmiedebergs Arch Pharmacol. 2022 Oct 13.
    Piperlongumine and bortezomib synergically inhibit cholangiocarcinoma via ER stress-induced cell death.
    Narathip Naradun, Krajang Talabnin, Kanyavee Issarangkul Na Ayuttha, Chutima Talabnin.
      Cholangiocarcinoma (CCA) is a lethal malignancy of the cholangiocytes lining the biliary tree. Only 25% of affected patients are eligible for resection due to late-stage diagnosis. Systemic chemotherapy is recommended for those inoperable patients; however, an inadequate response to such treatment remains a significant obstacle. Piperlongumine (PL) is a biologically active alkaloid that selectively kills various cancer cells through the induction of reactive oxygen species (ROS). The role of PL has been shown through its inhibiting the ubiquitin-proteasome system. The mechanism of PL-induced CCA cell death was investigated by inhibiting the UPS and testing the therapeutic potential of combining PL and the proteasome inhibitor bortezomib. A single treatment with PL or BTZ suppressed CCA cell growth. Combined treatment with PL with BTZ produced a synergistic interaction, evidenced by (1) a combination index of < 1 and (2) induction of cell cycle arrest and down-regulation of cell cycle markers. PL induced the accumulation of poly-ubiquitinated proteins in CCA cells but did not affect proteasome activity. PL, in combination with BTZ, amplified the accumulation of poly-ubiquitinated proteins in CCA cells, leading to an endoplasmic reticulum (ER) stress response through the induction of X-box binding protein mRNA splicing. Moreover, PL-combined BTZ promoted the activation of a proapoptotic unfolded protein response via the ATF4-CHOP axis. PL induced CCA cell death via increased accumulation of the poly-ubiquitinated proteins. PL also enhanced the anti-cancer activity of BTZ via ER stress-induced CCA cell death. Thus, the combination of PL and BTZ has potential as an alternative therapeutic option for CCA.
    Keywords:  Cholangiocarcinoma; Endoplasmic reticulum stress; Piperlongumine; Ubiquitin–proteasome system
    DOI:  https://doi.org/10.1007/s00210-022-02305-4
  2. Br J Cancer. 2022 Oct 13.
    Corynoxine suppresses pancreatic cancer growth primarily via ROS-p38 mediated cytostatic effects.
    Chunmei Wen, Qingqing Ruan, Zhaofeng Li, Xiang Zhou, Xuezhi Yang, Pingwei Xu, Percy David Papa Akuetteh, Zheng Xu, Jie Deng.
      BACKGROUND: Pancreatic cancer is among the most common malignant tumours, and effective therapeutic strategies are still lacking. While Corynoxine (Cory) can induce autophagy in neuronal cells, it remains unclear whether Cory has anti-tumour activities against pancreatic cancer.METHODS: Two pancreatic cancer cell lines, Patu-8988 and Panc-1, were used. Effects of Cory were evaluated by cell viability analysis, EdU staining, TUNEL assay, colony formation assay, and flow cytometry. Quantitative PCR and Western blot were performed to analyse mRNA and protein levels, respectively. In vivo anti-tumour efficacy of Cory was determined by a xenograft model.
    RESULTS: Cory treatment inhibited cell proliferation, induced endoplasmic reticulum (ER) stress, and triggered apoptosis in the pancreatic cancer cell lines. CHOP knockdown-mediated inhibition of ER stress alleviated the Cory-induced apoptosis but showed a limited effect on cell viability. Cory induced cell death partially via promoting reactive oxygen species (ROS) production and activating p38 signalling. Pretreatment with ROS scavenger N-acetylcysteine and p38 inhibitor SB203580 relieved the Cory-induced inhibition on cell growth. Cory remarkably blocked pancreatic tumour growth in vivo.
    CONCLUSIONS: Cory exerts an anti-tumour effect on pancreatic cancer primarily via ROS-p38-mediated cytostatic effects. Cory may serve as a promising therapeutic agent for pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41416-022-02002-2
  3. Oxid Med Cell Longev. 2022 ;2022 5424411
    Curcumin Enhanced Ionizing Radiation-Induced Immunogenic Cell Death in Glioma Cells through Endoplasmic Reticulum Stress Signaling Pathways.
    Zenghe Xiu, Ting Sun, Ying Yang, Yuping He, Shuangyu Yang, Xuefei Xue, Wei Yang.
      Objective: Local radiotherapy may cause distant tumor regression via inducing immunogenic cell death (ICD). Here, we investigated the effect of curcumin on ionizing radiation-induced immunogenic cell death in normoxic or hypoxic glioma cells and its mechanism in vitro and vivo.Methods: Hypoxic or normoxic glioma cell apoptosis and the cell surface exposure of calreticulin (CRT) were detected by flow cytometry. Extracellular ATP and HSP70 were measured by chemiluminescence assay and ELISA, respectively. Endoplasmic reticulum (ER) stress protein levels were detected by western blot. Moreover, the induction of bona fide ICD was detected by vaccination assays in mice bearing glioma model. Spleen lymphocytes and tumor-infiltrating lymphocyte subsets were analyzed by flow cytometry and immunohistochemistry.
    Results: Curcumin incubation before X-ray irradiation significantly increased radiation-induced apoptosis rate in normoxic or hypoxic glioma cells. Curcumin enhanced radiation-induced CRT exposure, release of HSP70 and ATP, and ER stress signaling activity. After treatment with ER stress pathway inhibitors, cell apoptosis and CRT exposure induced by the combination treatment of curcumin and X-ray were reduced. In vaccination experiments, glioma cells irradiated by X-ray produced a strong immunogenic response rejecting tumor formation in 70% mice. In comparison, cells treated by curcumin and X-ray produced a stronger immune response rejecting tumor formation in 90% mice. The combination treatment increased the percentage of tumor-infiltrating CD4+, CD8+ T lymphocytes, and CD11c+ dendritic cells compared to X-ray irradiation alone.
    Conclusion: Ionizing radiation-induced normoxic or hypoxic glioma immunogenic cell death could be further enhanced by curcumin through activating the ER stress PERK-eIF2α and IRE1α-XBP1 signaling pathways.
    DOI:  https://doi.org/10.1155/2022/5424411
  4. Biochim Biophys Acta Mol Basis Dis. 2022 Oct 11. pii: S0925-4439(22)00241-1. [Epub ahead of print] 166570
    Mitoregulin controls mitochondrial function and stress-adaptation response during early phase of endoplasmic reticulum stress in breast cancer cells.
    Munkyung Choi, Keon Wook Kang.
      The proper regulation of mitochondrial function is important for cellular homeostasis. Especially, in cancer cells, dysregulation of mitochondria is associated with diverse cellular events such as metabolism, redox status, and stress responses. Mitoregulin (MTLN), a micro protein encoded by LINC00116, recently has been reported to control mitochondrial functions in skeletal muscle cells and adipocytes. However, the role of MTLN in cancer cells remains unclear. In the present study, we found that MTLN regulates membrane potential and reactive oxygen species (ROS) generation of mitochondria in breast cancer cells. Moreover, MTLN deficiency resulted in abnormal mitochondria-associated ER membranes (MAMs) formation, which is crucial for stress adaptation. Indeed, the MTLN-deficient breast cancer cells failed to successfully resolve ER (endoplasmic reticulum) stress, and cell vulnerability to ER-stress inducers was significantly enhanced by the downregulation of MTLN. In conclusion, MTLN controls stress-adaptation responses in breast cancer cells as a key regulator of mitochondria-ER harmonization, and thereby its expression level may serve as an indicator of the responsiveness of cancer cells to proteasome inhibitors.
    Keywords:  ER stress; Mitochondria-associated ER membrane; Mitochondrial quality control; Mitoregulin
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166570
  5. Molecules. 2022 Oct 01. pii: 6491. [Epub ahead of print]27(19):
    Pllans-II Induces Cell Death in Cervical Cancer Squamous Epithelial Cells via Unfolded Protein Accumulation and Endoplasmic Reticulum Stress.
    Alejandro Montoya-Gómez, Nelson Rivera Franco, Leonel Ives Montealegre-Sanchez, Luis Manuel Solano-Redondo, Andrés Castillo, Mildrey Mosquera-Escudero, Eliécer Jiménez-Charris.
      Due to the lack of chemotherapeutic drugs that selectively affect cervical cancer cells, natural sources such as snake venom are currently being investigated for molecules with antitumor potential. Pllans-II, a phospholipase A2 type-Asp49 from Porthidium lansbergii lansbergii snake venom, induced cell death in a cervical cancer cell line-Ca Ski-related to dysfunction in the ability to resolve endoplasmic reticulum stress, evidenced by sub-expression of genes such as PERK, ERO1 PDIs, HSP70, and CHOP. Western blot analysis validated the last two genes' sub-expression at the protein level. In addition, Pllans-II presented a dose-dependent cytotoxic effect on cancer cells and an insignificant effect on healthy endothelial cells (HUVEC). Additionally, Pllans-II inhibited cancer cells' adhesion and migration capacity, induced cell cycle arrest in the G2/M phase, and induced apoptosis stimulated possibly by the extrinsic route. These results demonstrate for the first time that Pllans-II has an antitumor effect on a squamous epithelial cervical cancer cell line and represents a possible biotechnological tool for designing a prominent antitumor agent.
    Keywords:  antitumor potential; bioprospecting; phospholipase A2; snake venom; transcriptomic analysis
    DOI:  https://doi.org/10.3390/molecules27196491
  6. Biochem Pharmacol. 2022 Sep 19. pii: S0006-2952(22)00348-3. [Epub ahead of print]205 115254
    Diterpenoid DGA induces apoptosis via endoplasmic reticulum stress caused by changes in glycosphingolipid composition and inhibition of STAT3 in glioma cells.
    Tingting Kong, Zhenxue He, Shuying Wang, Chunxin Jiang, Fei Zhu, Jingjing Gao, Liu Li, Yanping Wang, Qing Xie, Yunsen Li.
      Glioma is one of the most common malignant primary brain tumors, with poor prognosis and high recurrence. There are currently few drugs approved for brain tumors; thus, it is necessary to develop new effective drugs. Natural diterpenoids have important biological activities, including antiinflammatory, antioxidative, and antitumor effects. In this study, 7α,14β-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione (DGA), a diterpenoid compound modified from glaucocalyxin A, inhibited the proliferation of many tumor cells, especially glioma. Flow cytometry analysis showed that DGA induced apoptosis in glioma cells. DGA also inhibited xenograft tumors in nude mice. It affected the expression of ceramide synthases (CerS) in glioma cells; CerS1 decreased, and CerS2 and CerS5 increased, resulting in a change in the composition of glycosphingolipids containing varying acyl chain lengths. In glioma cells treated with DGA, the gene transcription of activating transcription factor 4 (ATF4), X-box binding protein-1 (XBP1), and C/EBP-homologous protein (CHOP) in unfolded protein response pathways was upregulated. Meanwhile, the ratio of proapoptotic protein Bcl-2-associated X protein (BAX) to antiapoptotic protein B-cell lymphoma 2 (Bcl-2) also increased. This suggested that an imbalance of glycosphingolipids caused by DGA induced severe endoplasmic reticulum stress and triggered cell apoptosis. Moreover, Western blotting showed DGA inhibited the signal transducers and activators of transcription 3 (STAT3) signaling pathway by reducing the phosphorylation of STAT3 and its upstream kinases, which also promoted the apoptosis of glioma cells. Together, these results explored the anticancer activities of DGA and highlighted it as a potential candidate for treating glioma.
    Keywords:  Ceramide synthase; Endoplasmic reticulum stress; Glioma; Glycosphingolipid; STAT3
    DOI:  https://doi.org/10.1016/j.bcp.2022.115254
  7. J Zhejiang Univ Sci B. 2022 Oct 15. pii: 1673-1581(2022)10-0863-13. [Epub ahead of print]23(10): 863-875
    UPF1 increases amino acid levels and promotes cell proliferation in lung adenocarcinoma via the eIF2α-ATF4 axis.
    Lei Fang, Huan Qi, Peng Wang, Shiqing Wang, Tianjiao Li, Tian Xia, Hailong Piao, Chundong Gu.
      Up-frameshift 1 (UPF1), as the most critical factor in nonsense-mediated messenger RNA (mRNA) decay (NMD), regulates tumor-associated molecular pathways in many cancers. However, the role of UPF1 in lung adenocarcinoma (LUAD) amino acid metabolism remains largely unknown. In this study, we found that UPF1 was significantly correlated with a portion of amino acid metabolic pathways in LUAD by integrating bioinformatics and metabolomics. We further confirmed that UPF1 knockdown inhibited activating transcription factor 4 (ATF4) and Ser51 phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), the core proteins in amino acid metabolism reprogramming. In addition, UPF1 promotes cell proliferation by increasing the amino-acid levels of LUAD cells, which depends on the function of ATF4. Clinically, UPF1 mRNA expression is abnormal in LUAD tissues, and higher expression of UPF1 and ATF4 was significantly correlated with poor overall survival (OS) in LUAD patients. Our findings reveal that UPF1 is a potential regulator of tumor-associated amino acid metabolism and may be a therapeutic target for LUAD.
    Keywords:  Activating transcription factor 4 (ATF4); Amino acid metabolism; Lung adenocarcinoma; Up-frameshift 1 (UPF1)
    DOI:  https://doi.org/10.1631/jzus.B2200144
  8. Int J Mol Sci. 2022 Sep 24. pii: 11257. [Epub ahead of print]23(19):
    Polo-Like Kinase 2 Plays an Essential Role in Cytoprotection against MG132-Induced Proteasome Inhibition via Phosphorylation of Serine 19 in HSPB5.
    Shuji Ueda, Moeka Nishihara, Yuuki Hioka, Ken-Ichi Yoshino, Soichiro Yamada, Minoru Yamanoue, Yasuhito Shirai.
      Protein homeostasis, including protein folding, refolding, and degradation, is thought to decline with aging. HSPB5 (also known as αB-crystallin) prevents target protein aggregation as a molecular chaperone and exhibits a cytoprotective function against various cell stresses. To elucidate the effect of HSPB5 on endoplasmic reticulum (ER) stress, we searched for novel binding proteins of HSPB5 using the proximity-dependent biotin labeling method. Proteins presumed to interact with HSPB5 in cells treated with the proteasome inhibitor MG132 were identified by a reversible biotin-binding capacity method combining tamavidin2-REV magnetic beads and mass spectrometry. We discovered a new binding protein for HSPB5, polo-like kinase 2 (PLK2), which is an apoptosis-related enzyme. The expression of PLK2 was upregulated by MG132 treatment, and it was co-localized with HSPB5 near the ER in L6 muscle cells. Inhibition of PLK2 decreased ER stress-induced phosphorylation of serine 19 in HSPB5 and increased apoptosis by activation of caspase 3 under ER stress. Overexpression of HSPB5 (WT) suppressed the ER stress-induced caspase 3 activity, but this was not observed with phospho-deficient HSPB5 (3A) mutants. These results clarify the role of HSPB5 phosphorylation during ER stress and suggest that the PLK2/HSPB5 pathway plays an essential role in cytoprotection against proteasome inhibition-induced ER stress.
    Keywords:  BioID2; ER stress; MG132; PARP; PLK2; desmin-related cardiomyopathy; heat shock protein; tamavidin
    DOI:  https://doi.org/10.3390/ijms231911257
  9. Cell Mol Biol Lett. 2022 Oct 08. 27(1): 87
    Exosomal DNAJB11 promotes the development of pancreatic cancer by modulating the EGFR/MAPK pathway.
    Peng Liu, Fuqiang Zu, Hui Chen, Xiaoli Yin, Xiaodong Tan.
      Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with invasive and metastatic characteristics and poor prognosis. Intracellular protein homeostasis is associated with invasion and metastasis of pancreatic cancer, but the specific molecular mechanism remains unclear. Our previous studies have revealed that DNAJB11, a key protein in protein homeostasis, is secreted by exosomes in the supernatant of dissociated pancreatic cancer cells with high metastasis. The results from transcriptome sequencing and co-immunoprecipitation (Co-IP)-based liquid chromatography with tandem mass spectrometry (LC-MS/MS) showed that depletion of DNAJB11 levels could increase HSPA5 expression and induce endoplasmic reticulum stress through the PRKR-like endoplasmic reticulum kinase signaling pathway in pancreatic cancer cells. Furthermore, exosomal DNAJB11 promoted cell development of PC cells in vitro and in vivo. In addition, exosomal DNAJB11 could regulate the expression of EGFR and activate the downstream MAPK signaling pathway. Clinical blood samples were collected to evaluate the potential of exosome DNAJB11 as a diagnostic biomarker and therapeutic target for the treatment of pancreatic cancer. This study could provide a new theoretical basis and potential molecular targets for the treatment of pancreatic cancer.
    Keywords:  Early diagnosis; Exosomal protein; Pancreatic cancer; Signal transduction
    DOI:  https://doi.org/10.1186/s11658-022-00390-0
  10. Exp Cell Res. 2022 Oct 06. pii: S0014-4827(22)00369-X. [Epub ahead of print]421(1): 113376
    IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.
    Xike Mao, Chenxi Yu, Feng Yin, Wenjiao Xu, Yonghan Pan, Bowen Yang, Tao Huang, Siling Chen, Wenge Luo, Tianyu Su, Zhihao Wu.
      Mounting evidence indicates that activation of unfolded protein response (UPR) and metabolic reprogramming contribute to cancer cell migration and invasion, but the molecular mechanism of pro-EMT program through a coordinated action of UPR with metabolism has not been defined. In this study, we utilized ER stress-inducing reagent, thapsigargin (TG), to induced pharmacologic ER stress in lung cancer cells. Here. We report that the branch of UPR, IRE1α-XBP1 pathway plays a pivotal role in reprogramming lung cancer cell metabolism. At the molecular level, the expression of pyruvate dehydrogenase kinase-1 (PDK-1) is directly induced by XBP1 as a consequence of UPR activation, thus facilitating aerobic glycolysis and lactate production. We also demonstrated that PDK1 serves as a downstream element of UPR activation in induction of Snail and EMT program. In addition, PDK1-induced Snail was dependent on the lactate production derived from metabolic reprogramming. Our findings reveal a critical role of lactate in pro-invasion events and establishes a direct connection between ER-stress and metabolic reprogramming in facilitating cancer cell progression.
    Keywords:  IRE1α-XBP1 pathway; Metabolic reprogramming; Pyruvate dehydrogenase kinase-1 (PDK-1); Snail; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113376
  11. Front Cell Dev Biol. 2022 ;10 905911
    Corrigendum: Comprehensive analysis of the clinical and biological significances of endoplasmic reticulum stress in diffuse gliomas.
    Ruoyu Huang, Guanzhang Li, Kuanyu Wang, Zhiliang Wang, Fan Zeng, Huimin Hu, Tao Jiang.
      [This corrects the article DOI: 10.3389/fcell.2021.619396.].
    Keywords:  ER stress; glioma; prognosis; signature; tumor immune environment
    DOI:  https://doi.org/10.3389/fcell.2022.905911
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