bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2022‒11‒13
twelve papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto
  1. Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.
  2. Targeting the integrated stress response in hematologic malignancies.
  3. Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?
  4. Prodigiosin from Serratia Marcescens in Cockroach Inhibits the Proliferation of Hepatocellular Carcinoma Cells through Endoplasmic Reticulum Stress-Induced Apoptosis.
  5. Persistent endoplasmic reticulum stress stimulated by peptide assemblies for sensitizing cancer chemotherapy.
  6. Isorhamnetin Induces Apoptosis and Suppresses Metastasis of Human Endometrial Carcinoma Ishikawa Cells via Endoplasmic Reticulum Stress Promotion and Matrix Metalloproteinase-2/9 Inhibition In Vitro and In Vivo.
  7. Endoplasmic reticulum stress targeted therapy for breast cancer.
  8. An investigation of Sigma-1 receptor expression and ligand-induced endoplasmic reticulum stress in breast cancer.
  9. The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas.
  10. COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer.
  11. Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
  12. PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells.
  1. Cell Death Dis. 2022 Nov 10. 13(11): 951
    Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.
    Longhao Wang, Tao Hu, Zhibo Shen, Yuanyuan Zheng, Qishun Geng, Lifeng Li, Beibei Sha, Miaomiao Li, Yaxin Sun, Yongjun Guo, Wenhua Xue, Dan Xuan, Ping Chen, Jie Zhao.
      The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.
    DOI:  https://doi.org/10.1038/s41419-022-05341-3
  2. Exp Hematol Oncol. 2022 Nov 08. 11(1): 94
    Targeting the integrated stress response in hematologic malignancies.
    Gus O Nwosu, Jason A Powell, Stuart M Pitson.
      While numerous targeted therapies have been recently adopted to improve the treatment of hematologic malignancies, acquired or intrinsic resistance poses a significant obstacle to their efficacy. Thus, there is increasing need to identify novel, targetable pathways to further improve therapy for these diseases. The integrated stress response is a signaling pathway activated in cancer cells in response to both dysregulated growth and metabolism, and also following exposure to many therapies that appears one such targetable pathway for improved treatment of these diseases. In this review, we discuss the role of the integrated stress response in the biology of hematologic malignancies, its critical involvement in the mechanism of action of targeted therapies, and as a target for pharmacologic modulation as a novel strategy for the treatment of hematologic malignancies.
    Keywords:  ATF4; GCN2; HRI; Hematological malignancy; Integrated stress response; PERK; PKR; Targeted therapy
    DOI:  https://doi.org/10.1186/s40164-022-00348-0
  3. Cancers (Basel). 2022 Oct 29. pii: 5340. [Epub ahead of print]14(21):
    Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma?
    Guangqi Wang, Fengjuan Fan, Chunyan Sun, Yu Hu.
      Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.
    Keywords:  drug resistance; endoplasmic reticulum stress; multiple myeloma; unfolded protein response
    DOI:  https://doi.org/10.3390/cancers14215340
  4. Molecules. 2022 Oct 26. pii: 7281. [Epub ahead of print]27(21):
    Prodigiosin from Serratia Marcescens in Cockroach Inhibits the Proliferation of Hepatocellular Carcinoma Cells through Endoplasmic Reticulum Stress-Induced Apoptosis.
    Jie Wang, Hancong Liu, Liuchong Zhu, Jingyi Wang, Xiongming Luo, Wenbin Liu, Yan Ma.
      Hepatocellular carcinoma (HCC) is the most common primary liver malignant tumor, and the targeted therapy for HCC is very limited. Our previous study demonstrated that prodigiosin(PG), a secondary metabolite from Serratia marcescens found in the intestinal flora of cockroaches, inhibits the proliferation of HCC and increases the expression of CHOP, a marker protein for endoplasmic reticulum stress (ERS)-mediated apoptosis, in a dose-dependent manner. However, the mechanisms underlying the activity of PG in vivo and in vitro are unclear. This study explored the molecular mechanisms of PG-induced ERS against liver cancer in vitro and in vivo. The apoptosis of hepatocellular carcinoma cells induced by PG through endoplasmic reticulum stress was observed by flow cytometry, colony formation assay, cell viability assay, immunoblot analysis, and TUNEL assay. The localization of PG in cells was observed using laser confocal fluorescence microscopy. Flow cytometry was used to detect the intracellular Ca2+ concentration after PG treatment. We found that PG could promote apoptosis and inhibit the proliferation of HCC. It was localized in the endoplasmic reticulum of HepG2 cells, where it induces the release of Ca2+. PG also upregulated the expression of key unfolded response proteins, including PERK, IRE1α, Bip, and CHOP, and related apoptotic proteins, including caspase3, caspase9, and Bax, but down-regulated the expression of anti-apoptotic protein Bcl-2 in liver cancer. Alleviating ERS reversed the above phenomenon. PG had no obvious negative effects on the functioning of the liver, kidney, and other main organs in nude mice, but the growth of liver cancer cells was inhibited by inducing ERS in vivo. The findings of this study showed that PG promotes apoptosis of HCC by inducing ERS.
    Keywords:  PG; apoptosis; endoplasmic reticulum stress; hepatocellular carcinoma
    DOI:  https://doi.org/10.3390/molecules27217281
  5. Adv Healthc Mater. 2022 Nov 10. e2202039
    Persistent endoplasmic reticulum stress stimulated by peptide assemblies for sensitizing cancer chemotherapy.
    Na Song, Yanqiu Song, Binbin Hu, Xin Liu, Xiunan Yu, Hao Zhou, Jiafu Long, Zhilin Yu.
      Pharmacological targeting of endoplasmic reticulum (ER) stress represents one of important methods for disease therapy, which, however, is significantly suppressed by the ER homeostatic processes in cells. Herein we report a proof-of-concept strategy for persistent stimulation of ER stress via preventing ER stress adaptation by utilizing multifunctional peptide assemblies. The strategy was established via creation of peptide assemblies with ER-targeting and chaperone glucose-regulated protein 78 (GRP78)-inhibiting functions. The peptides assemblies formed well-defined nanofibers that were up-taken by human cervical cancer HeLa cells through an endo-/lysosome-mediated pathway and retrieved by ER organelles. The underlying mechanism studies unraveled that the ER-accumulated peptide assemblies simultaneously stimulated ER stress and inhibited GRP78 re-folding activity and thereby promoting endogenous protein aggregation. Combining the internalized peptide assemblies with the induced protein aggregates led to the persistent stimulation of ER stress without interference by GPR78. The persistent ER stress induced by the peptide assemblies bestows their application in sensitization of cancer chemotherapy. Both in vitro and in vivo results confirmed that the enhanced the cytotoxicity of drug toyocamycin against HeLa cells in the presence of peptide assemblies, thus efficiently sensitizing chemotherapy and inhibiting in vivo tumor growth. The strategy established in this study discloses the fundamental keys for efficient promotion of ER stress, thus providing the guidance for development of ER-targeting-assisted cancer chemotherapy in the future. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer Therapy; Chaperone Proteins; Endoplasmic Reticulum; Peptides; Self-Assembly
    DOI:  https://doi.org/10.1002/adhm.202202039
  6. Foods. 2022 Oct 28. pii: 3415. [Epub ahead of print]11(21):
    Isorhamnetin Induces Apoptosis and Suppresses Metastasis of Human Endometrial Carcinoma Ishikawa Cells via Endoplasmic Reticulum Stress Promotion and Matrix Metalloproteinase-2/9 Inhibition In Vitro and In Vivo.
    Lei Ye, Run-Hui Ma, Xiu-Xiu Zhang, Kiran Thakur, Jian-Guo Zhang, Mohammad Rizwan Khan, Rosa Busquets, Zhao-Jun Wei.
      Endometrial cancer (EC) is a very common female cancer which has attracted more and more attention. According to the individual patient's condition, the current treatment of EC patients is mainly based on surgery, which is supplemented by chemotherapy, radiotherapy, and endocrine intervention. However, these existing treatment strategies also have some inevitable limitations. Therefore, it is particularly important to find an active ingredient with low toxicity and a high safety profile against EC. Isorhamnetin is a flavonoid known to be present in a variety of plants, such as sea buckthorn, dry willow, and wolfberry. In recent years, the anti-tumor effects of isorhamnetin have been reported. In our study, isorhamnetin was shown to induce apoptosis in Ishikawa cells by inducing the endogenous mitochondrial apoptotic pathway and exogenous death receptor pathway, promoting the endoplasmic reticulum stress-related pathway, and activating the corresponding markers of UPR response. In addition, isorhamnetin affected the expression of MMP2 and MMP9-related proteins in vitro and in vivo and eventually repressed metastasis. Therefore, isorhamnetin can be used as a promising medicinal material for the treatment of EC.
    Keywords:  Ishikawa; UPR response; endometrial cancer; isorhamnetin; mitochondria
    DOI:  https://doi.org/10.3390/foods11213415
  7. Cell Commun Signal. 2022 Nov 07. 20(1): 174
    Endoplasmic reticulum stress targeted therapy for breast cancer.
    Di Xu, Zhen Liu, Ming-Xing Liang, Yin-Jiao Fei, Wei Zhang, Yang Wu, Jin-Hai Tang.
      Recurrence, metastasis, and drug resistance are still big challenges in breast cancer therapy. Internal and external stresses have been proven to substantially facilitate breast cancer progression through molecular and systemic mechanisms. For example, endoplasmic reticulum stress (ERS) results in activation of the unfolded protein response (UPR), which are considered an important cellular stress response. More and more reports indicate its key role in protein homeostasis and other diverse functions involved in the process of breast cancer progression. Therefore, therapies targeting the activation of ERS and its downstream signaling pathways are potentially helpful and novel tools to counteract and fight breast cancer. However, recent advances in our understanding of ERS are focused on characterizing and modulating ERS between healthy and disease states, and so little attention has been paid to studying the role and clinical application of targeting ERS in a certain cancer. In this review, we summarize the function and main mechanisms of ERS in different molecular types of breast cancer, and focus on the development of agents targeting ERS to provide new treatment strategies for breast cancer. Video Abstract.
    Keywords:  Anticancer drugs; Breast cancer; Endoplasmic reticulum stress; Signaling pathway; Unfolded protein response
    DOI:  https://doi.org/10.1186/s12964-022-00964-7
  8. Cancer Gene Ther. 2022 Nov 09.
    An investigation of Sigma-1 receptor expression and ligand-induced endoplasmic reticulum stress in breast cancer.
    Preeti Borde, Nicola Cosgrove, Sara Charmsaz, Stephen T Safrany, Leonie Young.
      Targeted therapeutic options and prognostic biomarkers for hormone receptor- or Her2 receptor-negative breast cancers are severely limited. The sigma-1 receptor, a stress-activated chaperone, is frequently dysregulated in disease. However, its significance in breast cancer (BCa) has not been adequately explored. Here, we report that the sigma-1 receptor gene (SIGMAR1) is elevated in BCa, particularly in the aggressive triple-negative (TNBC) subtype. By examining several patient datasets, we found that high expression at both the gene (SIGMAR1) and protein (Sig1R) levels associated with poor survival outcomes, specifically in ER-Her2- groups. Our data further show that high SIGMAR1 was predictive of shorter survival times in patients treated with adjuvant chemotherapy (ChT). Interestingly, in a separate cohort who received neoadjuvant taxane + anthracycline treatment, elevated SIGMAR1 associated with higher rates of pathologic complete response (pCR). Treatment with a Sig1R antagonist, 1-(4-iodophenyl)-3-(2-adamantyl)guanidine (IPAG), activated the unfolded protein response (UPR) in TNBC (high-Sig1R expressing) and ER + (low-Sig1R expressing) BCa cell lines. In tamoxifen-resistant LY2 cells, IPAG caused Sig1R to aggregate and co-localise with the stress marker BiP. These findings showcase the potential of Sig1R as a novel biomarker in TNBC as well as highlight its ligand-induced interference with the stress-coping mechanisms of BCa cells.
    DOI:  https://doi.org/10.1038/s41417-022-00552-4
  9. Int J Mol Sci. 2022 Oct 28. pii: 13067. [Epub ahead of print]23(21):
    The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas.
    Zhenye Li, Yiyuan Chen, Xiaohui Yao, Qian Liu, Haibo Zhu, Yazhuo Zhang, Jie Feng, Hua Gao.
      Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2β (EIF2β) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2β in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2β was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p < 0.001) for EIF2β and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p < 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p < 0.001) for GCN2, and r = 0.732 (p < 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2β was greater than that in patients with a low EIF2β (7/10 vs. 4/18, p = 0.038), with a lower immune-cell infiltration probability (p < 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p < 0.001). In in vitro experiments, the knockdown of EIF2β changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies.
    Keywords:  EIF2; integrated stress response; somatotroph adenomas; tumorigenesis
    DOI:  https://doi.org/10.3390/ijms232113067
  10. Cancer Lett. 2022 Nov 03. pii: S0304-3835(22)00482-7. [Epub ahead of print] 215995
    COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer.
    Shu-Yang Wang, Ling-Jie Zhang, Guo-Jun Chen, Qi-Qi Ni, Yuan Huang, Dan Zhang, Fang-Yi Han, Wen-Feng He, Li-Ling He, Yan-Qing Ding, Hong-Li Jiao, Ya-Ping Ye.
      RNA editing is among the most common RNA level modifications for generating amino acid changes. We identified a COPA A-to-I RNA editing event in CRC metastasis. Our results showed that the COPA A-to-I RNA editing rate was significantly increased in metastatic CRC tissues and was closely associated with aggressive tumors in the T and N stages. The COPA I164V protein damaged the Golgi-ER reverse transport function, induced ER stress, promoted the translocation of the transcription factors ATF6, XBP1 and ATF4 into the nucleus, and activated the expression of MALAT1, MET, ZEB1, and lead to CRC cell invasion and metastasis. Moreover, the COPA A-to-I RNA editing rate was positively correlated with the immune infiltration score. Collectively, the COPA I164V protein hijacked ER stress to promote the metastasis of CRC, and the COPA A-to-I RNA editing rate may be a potential predictor for patient response to immune checkpoint inhibitor (ICIs) treatment.
    Keywords:  COPA; ER stress; Immune checkpoint inhibitors (ICIs); RNA editing
    DOI:  https://doi.org/10.1016/j.canlet.2022.215995
  11. Cell Metab. 2022 Nov 02. pii: S1550-4131(22)00461-2. [Epub ahead of print]
    Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
    Zaili Yang, Yazhen Huo, Shixin Zhou, Jingya Guo, Xiaotu Ma, Tao Li, Congli Fan, Likun Wang.
      A hostile microenvironment in tumor tissues disrupts endoplasmic reticulum homeostasis and induces the unfolded protein response (UPR). A chronic UPR in both cancer cells and tumor-infiltrating leukocytes could facilitate the evasion of immune surveillance. However, how the UPR in cancer cells cripples the anti-tumor immune response is unclear. Here, we demonstrate that, in cancer cells, the UPR component X-box binding protein 1 (XBP1) favors the synthesis and secretion of cholesterol, which activates myeloid-derived suppressor cells (MDSCs) and causes immunosuppression. Cholesterol is delivered in the form of small extracellular vesicles and internalized by MDSCs through macropinocytosis. Genetic or pharmacological depletion of XBP1 or reducing the tumor cholesterol content remarkably decreases MDSC abundance and triggers robust anti-tumor responses. Thus, our data unravel the cell-non-autonomous role of XBP1/cholesterol signaling in the regulation of tumor growth and suggest its inhibition as a useful strategy for improving the efficacy of cancer immunotherapy.
    Keywords:  ER stress; HMGCR; IRE1α; MDSC; XBP1; cancer immunosuppression; cholesterol; macropinocytosis; small extracellular vesicle; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cmet.2022.10.010
  12. Cancer Treat Res Commun. 2022 Sep 27. pii: S2468-2942(22)00135-6. [Epub ahead of print]33 100644
    PRP-1, a toll-like receptor ligand, upregulates the unfolded protein response in human chondrosarcoma cells.
    Karina Galoian, Victoria Dahl, Andres Perez, Carina Denny, Beatrice Becker, Anil Sedani, Alexandra Moran, Daniel Martinez, Aaron Hoyt, Jeffrey Brown.
      BACKGROUND: Previous studies showed that proline-rich polypeptide (PRP-1) is a ligand for innate immunity toll-like receptors (TLR), and an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) which induces the death of chondrosarcoma cancer stem cells (CSC). The aim of this study was to investigate the effect of PRP-1 on the regulation of unfolded protein response (UPR) in human chondrosarcoma cells.MATERIALS AND METHODS: Lysates were prepared from a monolayer (bulk or ALDHhigh population), or spheroids chondrosarcoma cell cultures and treated with PRP-1 or control, followed by protein levels quantification by western blotting and mRNA expression by RT-qPCR of protein-RNA-like endoplasmic reticulum kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP), activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1α), and X-box binding protein (XBP1).
    RESULTS: The PRP-1 has been shown to increase the expression of PERK, eIF2α, ATF4, CHOP, ATF6, IRE1α, and XBP1, on both protein and mRNA levels.
    CONCLUSION: PRP-1 activated UPR branches in monolayer, spheroid, and stem cell populations of human chondrosarcoma.
    Keywords:  Cellular stress; Chondrosarcoma; Proline-rich polypeptide (PRP-1); Toll-like receptors; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.ctarc.2022.100644
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