bims-istrec 2022-09-25 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022–09–25
eight papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto

Construction of an endoplasmic reticulum stress-related gene model for predicting prognosis and immune features in kidney renal clear cell carcinoma.
Establishment of an endoplasmic reticulum stress-related signature predicting outcomes of gastric adenocarcinoma patients.
Cordycepin enhances radiosensitivity to induce apoptosis through cell cycle arrest, caspase pathway and ER stress in MA-10 mouse Leydig tumor cells.
Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.
The "Yin and Yang" of Unfolded Protein Response in Cancer and Immunogenic Cell Death.
EGCG Enhances the Chemosensitivity of Colorectal Cancer to Irinotecan through GRP78-MediatedEndoplasmic Reticulum Stress.
Stress-mediated attenuation of translation undermines T-cell activity in cancer.
Biomimetic Polymeric Nanoparticle-Mediated Chemotherapy Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

Front Mol Biosci. 2022 ;9 928006

Construction of an endoplasmic reticulum stress-related gene model for predicting prognosis and immune features in kidney renal clear cell carcinoma.

Yuanhao Shen, Yinghao Cao, Lei Zhou, Jianfeng Wu, Min Mao.

  Background: Kidney renal clear cell carcinoma (KIRC) is one of the most lethal malignant tumors with a propensity for poor prognosis and difficult treatment. Endoplasmic reticulum (ER) stress served as a pivotal role in the progression of the tumor. However, the implications of ER stress on the clinical outcome and immune features of KIRC patients still need elucidation. Methods: We identified differentially expressed ER stress-related genes between KIRC specimens and normal specimens with TCGA dataset. Then, we explored the biological function and genetic mutation of ER stress-related differentially expressed genes (DEGs) by multiple bioinformatics analysis. Subsequently, LASSO analysis and univariate Cox regression analysis were applied to construct a novel prognostic model based on ER stress-related DEGs. Next, we confirmed the predictive performance of this model with the GEO dataset and explored the potential biological functions by functional enrichment analysis. Finally, KIRC patients stratified by the prognostic model were assessed for tumor microenvironment (TME), immune infiltration, and immune checkpoints through single-sample Gene Set Enrichment Analysis (ssGSEA) and ESTIMATE analysis. Results: We constructed a novel prognostic model, including eight ER stress-related DEGs, which could stratify two risk groups in KIRC. The prognostic model and a model-based nomogram could accurately predict the prognosis of KIRC patients. Functional enrichment analysis indicated several biological functions related to the progression of KIRC. The high-risk group showed higher levels of tumor infiltration by immune cells and higher immune scores. Conclusion: In this study, we constructed a novel prognostic model based on eight ER stress-related genes for KIRC patients, which would help predict the prognosis of KIRC and provide a new orientation to further research studies on personalized immunotherapy in KIRC.

Keywords:  endoplasmic reticulum stress; immunotherapy; kidney renal clear cell carcinoma; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fmolb.2022.928006
Front Genet. 2022 ;13 944105

Establishment of an endoplasmic reticulum stress-related signature predicting outcomes of gastric adenocarcinoma patients.

Meiyuan Gong, Jingtao Wang, Wenfang Gao, Qian Liu, Jiaxing Chen, Guojun Wang, Qi Zhang.

  Background: Gastric adenocarcinoma (GAC) is a common clinical malignancy with a poor prognosis. Endoplasmic reticulum (ER) stress plays important roles in the progression, immune filtration, and chemoresistance of cancers. However, whether ER stress-related gene signatures can predict the prognosis of GAC patients remains unknown. Methods: GAC patient RNA-seq data downloaded from The Cancer Genome Atlas and gastric cancer patient microarray data from Gene Expression Omnibus datasets were analyzed using LASSO regression to construct an ER stress-related signature. Survival analysis, time-dependent receiver operating characteristic (ROC) curves, and Cox regression analysis were used to verify the efficacy of the signature. Immune infiltration, somatic mutation, immune checkpoint, and copy number variation analyses were utilized to explore the potential biological significance of the signature. Results: In the present study, eight ER stress-related gene signatures were constructed. Survival analysis showed that patients in the high-risk group had a significantly worse prognosis. The area under the time-dependent ROC curves was 0.65, 0.70, and 0.63 at 1, 3, and 5 years, respectively, in the training cohort. Cox regression analysis showed that the signature is an independent prognostic factor. To predict GAC patients' prognosis meeting individual needs, a nomogram was constructed with good accuracy. In addition, gene set enrichment and immune infiltration analyses showed that the ER stress-related signature is associated with cancer-related pathway activation and an immunosuppressive tumor microenvironment in GAC. Conclusion: In the current study, we established an ER stress-related signature. This prognostic signature has good predictive power and could facilitate the development of novel strategies for the clinical treatment of GAC.

Keywords:  endoplasmic reticulum stress; gastric adenocarcinoma; immune checkpoint inhibitors; immune filtration; prognostic signature

DOI:  https://doi.org/10.3389/fgene.2022.944105
Am J Cancer Res. 2022 ;12(8): 3601-3624

Cordycepin enhances radiosensitivity to induce apoptosis through cell cycle arrest, caspase pathway and ER stress in MA-10 mouse Leydig tumor cells.

Yi-Ping Lee, Wei-Ru Huang, Wun-Syuan Wu, Yuan-Hua Wu, Sheng-Yow Ho, Ying-Jan Wang, Bu-Miin Huang.

Radiotherapy is a localized treatment commonly used in various types of cancer. However, major limitation of radiotherapy is the development of resistance of tumor cells to radiosensitivity. Cordycepin, a predominant functional component of the Cordyceps sinensis, is considered to use in treating tumor cells. In the present study, we investigated the anticancer effect of the combination of radiation and cordycepin in the treatment of Leydig tumor cells. Results showed that the combination treatment has a synergistic effect significantly suppress cell viability and enhance the radiosensitivity in MA-10 mouse Leydig tumor cells. The combination treatment induced MA-10 cell apoptosis through increasing levels of cleaved caspase-3/-8/-9, poly ADP-ribose polymerase (PARP), and cytochrome c and decreasing levels of B-cell lymphoma 2 (Bcl-2). In addition, prolonged sub-G1 and G2/M arrest accompany with cell cycle-related protein regulation was observed in cells that received the combination treatment. The endoplasmic reticulum (ER) stress-related protein expressions were regulated after MA-10 cells treating with a combination of 100 μM cordycepin and 4 Gy radiation. Furthermore, the combination treatment also decreased the Leydig tumor mass by increasing cell apoptosis in tumor-bearing mice. In conclusion, cordycepin enhances radiosensitivity to induce mouse Leydig tumor cells toward apoptosis in vitro and in vivo. This study will provide a scientific basis for the development of therapeutic regimen of testicular cancer.

Keywords: Cordycepin; ER stress; Leydig tumor cell; MA-10 cell; apoptosis; caspase; cell cycle; radiation
Cancer Cell. 2022 Aug 29. pii: S1535-6108(22)00380-4. [Epub ahead of print]

Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.

Jessica K Mandula, Shiun Chang, Eslam Mohamed, Rachel Jimenez, Rosa A Sierra-Mondragon, Darwin C Chang, Alyssa N Obermayer, Carlos M Moran-Segura, Satyajit Das, Julio A Vazquez-Martinez, Karol Prieto, Ann Chen, Keiran S M Smalley, Brian Czerniecki, Peter Forsyth, Richard C Koya, Brian Ruffell, Juan R Cubillos-Ruiz, David H Munn, Timothy I Shaw, Jose R Conejo-Garcia, Paulo C Rodriguez.

  Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.

Keywords:  PERK; immunogenic cell death; tumor immunity; type I IFN; unfolded protein responses

DOI:  https://doi.org/10.1016/j.ccell.2022.08.016
Cells. 2022 Sep 16. pii: 2899. [Epub ahead of print]11(18):

The "Yin and Yang" of Unfolded Protein Response in Cancer and Immunogenic Cell Death.

Nicole Rufo, Yihan Yang, Steven De Vleeschouwer, Patrizia Agostinis.

  Physiological and pathological burdens that perturb endoplasmic reticulum homeostasis activate the unfolded protein response (UPR), a conserved cytosol-to-nucleus signaling pathway that aims to reinstate the vital biosynthetic and secretory capacity of the ER. Disrupted ER homeostasis, causing maladaptive UPR signaling, is an emerging trait of cancer cells. Maladaptive UPR sustains oncogene-driven reprogramming of proteostasis and metabolism and fosters proinflammatory pathways promoting tissue repair and protumorigenic immune responses. However, when cancer cells are exposed to conditions causing irreparable ER homeostasis, such as those elicited by anticancer therapies, the UPR switches from a survival to a cell death program. This lethal ER stress response can elicit immunogenic cell death (ICD), a form of cell death with proinflammatory traits favoring antitumor immune responses. How UPR-driven pathways transit from a protective to a killing modality with favorable immunogenic and proinflammatory output remains unresolved. Here, we discuss key aspects of the functional dichotomy of UPR in cancer cells and how this signal can be harnessed for therapeutic benefit in the context of ICD, especially from the aspect of inflammation aroused by the UPR.

Keywords:  ER stress; ICD; UPR; cancer; immunogenic cell death; inflammation

DOI:  https://doi.org/10.3390/cells11182899
J Oncol. 2022 ;2022 7099589

EGCG Enhances the Chemosensitivity of Colorectal Cancer to Irinotecan through GRP78-MediatedEndoplasmic Reticulum Stress.

Wenbing Wu, Hui Gou, Bin Xiang, Ruiman Geng, Jingying Dong, Xiaolong Yang, Dan Chen, Rongyang Dai, Lihong Chen, Ji Liu.

This study aimed to explore the role of GRP78-mediated endoplasmic reticulum stress (ERS) in the synergistic inhibition of colorectal cancer by epigallocatechin-3-gallate (EGCG) and irinotecan (IRI). Findings showed that EGCG alone or in combination with irinotecan can significantly promote intracellular GRP78 protein expression, reduce mitochondrial membrane potential and intracellular ROS in RKO and HCT 116 cells, and induce cell apoptosis. In addition, glucose regulatory protein 78 kDa (GRP78) is significantly over-expressed in both colorectal cancer (CRC) tumor specimens and mouse xenografts. The inhibition of GRP78 by small interfering RNA led to the decrease of the sensitivity of CRC cells to the drug combination, while the overexpression of it by plasmid significantly increased the apoptosis of cells after the drug combination. The experimental results in the mouse xenografts model showed that the combination of EGCG and irinotecan could inhibit the growth of subcutaneous tumors of HCT116 cells better than the two drugs alone. EGCG can induce GRP78-mediated endoplasmic reticulum stress and enhance the chemo-sensitivity of colorectal cancer cells when coadministered with irinotecan.

DOI: https://doi.org/10.1155/2022/7099589
Cancer Res. 2022 Sep 20. pii: CAN-22-1744. [Epub ahead of print]

Stress-mediated attenuation of translation undermines T-cell activity in cancer.

Brian P Riesenberg, Elizabeth G Hunt, Megan D Tennant, Katie E Hurst, Alex M Andrews, Lee R Leddy, David M Neskey, Elizabeth G Hill, Guillermo O Rangel Rivera, Chrystal M Paulos, Peng Gao, Jessica E Thaxton.

Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2a. Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2a undermines the ability of T cells to suppress tumor growth. Reprogramming T cell metabolism was able to alleviate p-eIF2a accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2a to support optimal antitumor T cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1744
Adv Mater. 2022 Sep 20. e2206861

Biomimetic Polymeric Nanoparticle-Mediated Chemotherapy Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

Yunqi Guo, Yu Fan, Zhiqiang Wang, Gaoming Li, Mengsi Zhan, Junli Gong, Jean-Pierre Majoral, Xiangyang Shi, Mingwu Shen.

  Construction of multifunctional nanoplatforms to elevate chemotherapeutic efficacy and induce long-term antitumor immunity still remains to be an extreme challenge. Herein, we report the design of an advanced redox-responsive nanomedicine formulation based on phosphorus dendrimer-copper(II) complexes (1G3 -Cu)- and toyocamycin (Toy)-loaded polymeric nanoparticles (GCT NPs) coated with cancer cell membranes (CM). The designed GCT@CM NPs with a size of 210 nm are stable under a physiological condition but are rapidly dissociated in the reductive tumor microenvironment to deplete glutathione and release drugs. The co-loading of 1G3 -Cu and Toy within the NPs causes significant tumor cell apoptosis and immunogenic cell death through 1G3 -Cu-induced mitochondrial dysfunction and Toy-mediated amplification of endoplasmic reticulum stress, respectively, thus effectively suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor-infiltrating cytotoxic T lymphocytes. Likewise, the coated CM and the loaded 1G3 -Cu render the GCT@CM NPs with homotypic targeting and T1 -weighted magnetic resonance imaging of tumors, respectively. With the assistance of programmed cell death ligand 1 antibody, the GCT@CM NP-mediated chemotherapy can significantly potentiate tumor immunotherapy for effective inhibition of tumor recurrence and metastasis. The developed GCT@CM NPs hold a great potential for chemotherapy-potentiated immunotherapy of different tumor types through different mechanisms or synergies. This article is protected by copyright. All rights reserved.

Keywords:  chemotherapy-potentiated immunotherapy; immunogenic cell death; phosphorus dendrimers; redox-responsiveness; toyocamycin

DOI:  https://doi.org/10.1002/adma.202206861