bims-istrec 2022-09-18 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022–09–18
eight papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto

Development and validation of a prognosis prediction model based on 18 endoplasmic reticulum stress-related genes for patients with lung adenocarcinoma.
Myricetin activates the Caspase-3/GSDME pathway via ER stress induction of pyroptosis in lung cancer cells.
The UCHL5 inhibitor b-AP15 overcomes cisplatin resistance via suppression of cancer stemness in urothelial carcinoma.
An integrative systems biology approach to overcome venetoclax resistance in acute myeloid leukemia.
Development and validation of a novel endoplasmic reticulum stress-related lncRNA prognostic signature and candidate drugs in breast cancer.
GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis.
Metabolic targeting of NRF2 potentiates the efficacy of the TRAP1 inhibitor G-TPP through reduction of ROS detoxification in colorectal cancer.
Pediatric glioblastoma cells are sensitive to drugs that inhibit eIF2α dephosphorylation and its phosphomimetic S51D variant.

Front Oncol. 2022 ;12 902353

Development and validation of a prognosis prediction model based on 18 endoplasmic reticulum stress-related genes for patients with lung adenocarcinoma.

Long Shu, Shuang Liu, Yongguang Tao.

   Background: Endoplasmic reticulum (ER) stress had a crucial impact on cell survival, proliferation, and metastasis in various cancers. However, the role of ER stress in lung adenocarcinoma remains unclear.
Method: Gene expression and clinical data of lung adenocarcinoma (LUAD) samples were extracted from The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets. ER stress score (ERSS) was constructed based on hub genes selected from 799 ER stress-related genes by least absolute shrinkage and selection operator (LASSO) regression. A Cox regression model, integrating ERSS and the TNM stage, was developed to predict overall survival (OS) in TCGA cohort and was validated in GEO cohorts. Gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA), and gene mutation analyses were performed to further understand the molecular features of ERSS. The tumor immune infiltration was evaluated by ESTIMATE, CIBERSORT, and xCell algorithms. The receiver operating characteristic (ROC) curves were used to evaluate the predictive value of the risk model. p< 0.05 was considered statistically significant.
Results: One hundred fifty-seven differentially expressed genes (DEGs) were identified between tumor and para-carcinoma tissues, and 45 of them significantly correlated with OS. Next, we identified 18 hub genes and constructed ERSS by LASSO regression. Multivariate analysis demonstrated that higher ERSS (p< 0.0001, hazard ratio (HR) = 3.8, 95%CI: 2.8-5.2) and TNM stage (p< 0.0001, HR = 1.55, 95%CI: 1.34-1.8) were independent predictors for worse OS. The prediction model integrating ERSS and TNM stage performed well in TCGA cohort (area under the curve (AUC) at five years = 0.748) and three GEO cohorts (AUC at 5 years = 0.658, 0.717, and 0.739). Pathway enrichment analysis showed that ERSS significantly correlated with unfolded protein response. Meanwhile, pathways associated with the cell cycle, growth, and metabolism were significantly enriched in the high ERSS group. Patients with SMARCA4, TP53, and EGFR mutations showed significantly higher ERSS (p = 4e-04, 0.0027, and 0.035, respectively). Tissues with high ERSS exhibited significantly higher infiltration of M1 macrophages, activated dendritic cells, and lower infiltration of CD8+ T cells and B cells, which indicate an activated tumor antigen-presenting but suppressive immune response status.
Conclusion: We developed and validated an ER stress-related risk model that exhibited great predictive value for OS in patients with LUAD. Our work also expanded the understanding of the role of ER stress in LUAD.

Keywords:  GEO; TCGA; endoplasmic reticulum stress; lung adenocarcinoma; prediction model

DOI:  https://doi.org/10.3389/fonc.2022.902353
Front Pharmacol. 2022 ;13 959938

Myricetin activates the Caspase-3/GSDME pathway via ER stress induction of pyroptosis in lung cancer cells.

Jicheng Han, Cheng Cheng, Jinxin Zhang, Jinbo Fang, Wei Yao, Yilong Zhu, Zhiru Xiu, Ningyi Jin, Huijun Lu, Xiao Li, Yiquan Li.

  Pyroptosis is related to the occurrence, development, and therapeutic response of tumors, mediated by the proteins of the Gasdermin family. These proteins have become potential biomarkers for cancer treatment, and their agonists are likely to become a new direction in research and development of antitumor drugs. In this study, we found that myricetin has an inhibitory effect on lung cancer cells of the activation of pyroptosis. Analysis of the expression of Gasdermin family proteins revealed that this phenomenon was caused by the cleavage of GSDME. Subsequently, specific inhibitors, we found that caspase-3 was its upstream activation factor. In addition, mitochondrial and endoplasmic reticulum (ER) analysis showed that myricetin can cause endoplasmic reticulum stress and increase reactive oxygen species (ROS) levels. Subsequent inhibition of caspase-12 revealed that the expression levels of cleaved-caspase-3 and cleaved-GSDME were significantly reduced, resulting in the inhibition of pyroptosis. Using in vivo experiments, we also found that the treatment with myricetin can reduce tumor volume and significantly increase the level of pyroptosis-related proteins in tumor tissues. Overall, our findings show that myricetin induces cell death of lung cancer cells primarily through an ER stress pathway-induced pyroptosis. Therefore, myricetin has the potential to be used as a pyroptosis agonist in research and development of antitumor drugs.

Keywords:  GSDME; ROS; er stress; myricetin; pyroptosis

DOI:  https://doi.org/10.3389/fphar.2022.959938
Mol Ther Oncolytics. 2022 Sep 15. 26 387-398

The UCHL5 inhibitor b-AP15 overcomes cisplatin resistance via suppression of cancer stemness in urothelial carcinoma.

Po-Ming Chow, Jun-Ren Dong, Yu-Wei Chang, Kuan-Lin Kuo, Wei-Chou Lin, Shing-Hwa Liu, Kuo-How Huang.

  Urothelial carcinoma (UC) comprises the majority of bladder cancers. Standard platinum-based chemotherapy has a response rate of approximately 50%, but drug resistance develops after short-term treatment. Deubiquitinating (DUB) enzyme inhibitors increase protein polyubiquitination and endoplasmic reticulum (ER) stress, which might further suppress cancer stemness and overcome cisplatin resistance. Therefore, we investigated the cytotoxic effect and potential mechanisms of b-AP15 on urothelial carcinoma. Our results revealed that b-AP15 induced ER stress and apoptosis in BFTC905, T24, T24/R (cisplatin-resistant), and RT4 urothelial carcinoma cell lines. Inhibition of the MYC signaling pathway and cancer stemness by b-AP15 was confirmed by RNA sequencing, RT-PCR, immunoblotting, and sphere-forming assays. In the mouse xenograft model, the combination of b-AP15 and cisplatin showed superior therapeutic effects compared with either monotherapy.

Keywords:  ER stress; bladder cancer; cancer stem cell; chemoresistance; deubiquitination

DOI:  https://doi.org/10.1016/j.omto.2022.08.004
PLoS Comput Biol. 2022 Sep;18(9): e1010439

An integrative systems biology approach to overcome venetoclax resistance in acute myeloid leukemia.

Michelle Przedborski, David Sharon, Severine Cathelin, Steven Chan, Mohammad Kohandel.

The over-expression of the Bcl-2 protein is a common feature of many solid cancers and hematological malignancies, and it is typically associated with poor prognosis and resistance to chemotherapy. Bcl-2-specific inhibitors, such as venetoclax, have recently been approved for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, and they are showing promise in clinical trials as a targeted therapy for patients with relapsed or refractory acute myeloid leukemia (AML). However, successful treatment of AML with Bcl-2-specific inhibitors is often followed by the rapid development of drug resistance. An emerging paradigm for overcoming drug resistance in cancer treatment is through the targeting of mitochondrial energetics and metabolism. In AML in particular, it was recently observed that inhibition of mitochondrial translation via administration of the antibiotic tedizolid significantly affects mitochondrial bioenergetics, activating the integrated stress response (ISR) and subsequently sensitizing drug-resistant AML cells to venetoclax. Here we develop an integrative systems biology approach to acquire a deeper understanding of the molecular mechanisms behind this process, and in particular, of the specific role of the ISR in the commitment of cells to apoptosis. Our multi-scale mathematical model couples the ISR to the intrinsic apoptosis pathway in venetoclax-resistant AML cells, includes the metabolic effects of treatment, and integrates RNA, protein level, and cellular viability data. Using the mathematical model, we identify the dominant mechanisms by which ISR activation helps to overcome venetoclax resistance, and we study the temporal sequencing of combination treatment to determine the most efficient and robust combination treatment protocol.

DOI: https://doi.org/10.1371/journal.pcbi.1010439
Front Genet. 2022 ;13 949314

Development and validation of a novel endoplasmic reticulum stress-related lncRNA prognostic signature and candidate drugs in breast cancer.

Jiehui Cai, Zeqi Ji, Jinyao Wu, Lingzhi Chen, Daitian Zheng, Yaokun Chen, Xinkang Zhang, Wanchun Xie, Jieying Huang, Manqi Chen, Ru Lin, Weixun Lin, Yexi Chen, Zhiyang Li.

  Breast cancer (BC), the most common malignancy in women, has a high cancer-related mortality. Endoplasmic reticulum stress (ERS), a response to the accumulation of unfolded proteins, has emerging roles in tumorigenesis, including invasion, metastasis, immune escape, etc. However, few studies have focused on the correlation between ERS with long non-coding RNAs (lncRNAs) in BC. We attempted to construct an ERS-related lncRNA prognostic signature and study its value in BC from tumor mutational burden (TMB), tumor immune microenvironment (TIME), cluster, clinical treatment, and so on. In the present study, transcriptomic and clinical data of BC patients were extracted from The Cancer Genome Atlas (TCGA) database. Correlation test, Cox regression analysis, least absolute shrinkage, and selection operator (LASSO) method were performed to determine an ERS-related lncRNA prognostic signature. Survival and predictive performance were analyzed according to Kaplan-Meier curves and receiver operating characteristic (ROC) curves, while nomograms and calibration curves were established. Then, an enrichment analysis was performed to study the functions and biological processes of ERS-related lncRNAs. TMB and TIME were also analyzed to assess the mutational status and immune status. Additionally, by using consensus cluster analysis, we compared differences among tumor subtypes. Drug sensitivity analysis and immunologic efficacy evaluations were performed together for further exploration. We identified a novel prognostic signature consisting of 9 ERS-related lncRNAs. High-risk patients had worse prognoses. The signature had a good predictive performance as an independent prognostic indicator and was significantly associated with clinicopathological characteristics. Enrichment analysis showed that metabolic pathways were enriched in high-risk patients, while immune pathways were more active in low-risk patients. Low-risk patients had lower TMB, higher immune scores, and stronger immune functions. Cluster analysis clarified that cluster 2 had the most active immune functions and was sensitive to more drugs, which may have the best clinical immunological efficacy. A clinical efficacy evaluation revealed that patients in the low-risk group may benefit more from chemotherapy, targeted therapy, and immunotherapy. The novel signature has significant clinical implications in prognosis prediction for BC. Our study clarifies that there is a potential connection between the ERS-related lncRNAs and BC, which may provide new treatment guidelines for BC.

Keywords:  breast cancer; candidate drugs; endoplasmic reticulum stress; long non-coding RNA; prognostic signature; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fgene.2022.949314
Elife. 2022 Sep 15. pii: e81083. [Epub ahead of print]11

GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis.

Ricardo A Cordova, Jagannath Misra, Parth H Amin, Anglea J Klunk, Nur P Damayanti, Kenneth R Carlson, Andrew J Elmendorf, Hyeong-Geug Kim, Emily T Mirek, Bennet D Elzey, Marcus J Miller, X Charlie Dong, Liang Cheng, Tracy G Anthony, Robero Pili, Ronald C Wek, Kirk A Staschke.

  A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier (SLC) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.

Keywords:  cancer biology; cell biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.81083
Cancer Lett. 2022 Sep 13. pii: S0304-3835(22)00402-5. [Epub ahead of print] 215915

Metabolic targeting of NRF2 potentiates the efficacy of the TRAP1 inhibitor G-TPP through reduction of ROS detoxification in colorectal cancer.

Hong-Yuan Tsai, Mary P Bronner, Jordon K March, John F Valentine, Noah Freeman Shroyer, Lisa A Lai, Teresa A Brentnall, Sheng Pan, Ru Chen.

  Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 by G-TPP disrupted redox homeostasis and induced cell death. However, colon cancers show a wide range of responses to G-TPP treatment through the induction of variable ER stress responses and ROS accumulation. Interestingly, a strong inverse correlation was observed between the expression of TRAP1 and antioxidant genes in colon tumor tissues using the GSE106582 database. Using a luciferase reporter assay, we detected increased transcriptional activation of antioxidant response elements (AREs) in G-TPP-treated DLD1 and RKO cells but not in SW48 cells. We found that G-TPP induced upregulation of GRP78, CHOP and PARP cleavage in G-TPP-sensitive cells (SW48). In contrast, G-TPP treatment of G-TPP-resistant cells (DLD1 and RKO) resulted in excessive activation of the antioxidant gene NRF2, leading to ROS detoxification and improved cell survival. The NRF2 target genes HO1 and NQO1 were upregulated in G-TPP-treated DLD1 cells, making the cells more resistant to G-TPP treatment. Furthermore, treatment with both a NRF2 inhibitor and a TRAP1 inhibitor led to excessive ROS production and exacerbated G-TPP-induced cell death in G-TPP-resistant cells. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome colon cancer resistance by raising cellular ROS levels above the cytotoxic threshold.

Keywords:  CHOP; Colon cancer; NRF2; ROS; TRAP1

DOI:  https://doi.org/10.1016/j.canlet.2022.215915
Front Oncol. 2022 ;12 959133

Pediatric glioblastoma cells are sensitive to drugs that inhibit eIF2α dephosphorylation and its phosphomimetic S51D variant.

Karin Eytan, Ziv Versano, Roni Oren, Jasmine Jacob-Hirsch, Moshe Leitner, Alon Harmelin, Gideon Rechavi, Amos Toren, Shoshana Paglin, Michal Yalon.

  We found that pediatric glioblastoma (PED-GBM) cell lines from diffuse intrinsic pontine glioma (DIPG) carrying the H3K27M mutation or from diffuse hemispheric glioma expressing the H3G34R mutation are sensitive to the combination of vorinostat (a histone deacetylase inhibitor) and PARP-1 inhibitors. The combined treatment increased the phosphorylation of eIF2α (P-eIF2α) relative to each drug alone and enhanced the decrease in cell survival. To explore the role played by increased P-eIF2α in modulating PED-GBM survival and response to treatments, we employed brain-penetrating inhibitors of P-eIF2α dephosphorylation: salubrinal and raphin-1. These drugs increased P-eIF2α, DNA damage, and cell death, similarly affecting the sensitivity of DIPG cells and derived neurospheres to PARP-1 inhibitors. Interestingly, these drugs also decreased the level of eIF2Bϵ (the catalytic subunit of eIF2B) and increased its phosphorylation, thereby enhancing the effect of increased P-eIF2α. Transient transfection with the S51D phosphomimetic eIF2α variant recapitulated the effect of salubrinal and raphin-1 on PED-GBM survival and sensitivity to PARP-1 inhibitors. Importantly, either salubrinal or raphin-1 dramatically increased the sensitivity of DIPG cells to radiation, the main treatment modality of PED-GBM. Finally, PED-GBM was more sensitive than normal human astrocytes to salubrinal, raphin-1, and the treatment combinations described herein. Our results indicate that combinations of histone deacetylase inhibitors and PARP-1 inhibitors should be evaluated for their toxicity and efficacy in PED-GBM patients and point to drugs that increase P-eIF2α or modulate its downstream effectors as a novel means of treating PED-GBM.

Keywords:  DIPG; PARP-1; eIF2α phosphorylation; pediatric glioblastoma; raphin-1; salubrinal

DOI:  https://doi.org/10.3389/fonc.2022.959133