Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity

Salvagno, Camilla; Mandula, Jessica; Rodríguez, Paulo C.; Cubillos-Ruiz, Juan R.

doi:10.1016/j.trecan.2022.06.006

Cited by 51 publications

(26 citation statements)

References 125 publications

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“…To validate the presence of ER stress and activation of unfolded protein response (UPR) after propofol treatment in osteosarcoma, all three pathways [ 20 ] were examined by testing the protein level of CHOP and p-eIF2 α together with the presence of XBP1s mRNA. XBP1s is a truncate isoform produced by splicing of 26 nucleotides from the central part of the mRNA of XBP1.…”

Section: Discussionmentioning

confidence: 99%

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Propofol Regulates ER Stress to Inhibit Tumour Growth and Sensitize Osteosarcoma to Doxorubicin

Hua

Zhao

et al. 2023

International Journal of Clinical Practice

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Osteosarcoma is the most common malignant bone tumour affecting children and young adults. The antitumour role of propofol, a widely used intravenous sedative-hypnotic agent, has been recently reported in different cancer types. In this study, we aimed to assess the role of propofol on osteosarcoma and explore the possible mechanisms. Propofol of increasing concentrations (2.5, 5, 10, and 20 μg/ml) was used to treat the MG63 and 143B cells for 72 hours, and the CCK8 assay was applied to evaluate the tumour cell proliferation. Tumour cell migration and invasion were assessed with the transwell assay. The tumour cells were also treated with doxorubicin single agent or in combination with propofol to explore their synergic role. Differential expressed genes after propofol treatment were obtained and functionally assessed with bioinformatic tools. Expression of ER stress markers CHOP, p-eIF2α, and XBP1s was evaluated to validate the activation of ER stress response with western blot and qRT-PCR. The statistical analyses were performed with R v4.2.1. Propofol treatment led to significant growth inhibition in MG63 and 143B cells in a dose-dependent manner ( p < 0.05 ). Osteosarcoma migration (MG63 91.4 (82–102) vs. 56.8 (49–65), p < 0.05 ; 143B 96.6 (77–104) vs. 45.4 (28–54), p < 0.05 ) and invasion (MG63 68.6 (61–80) vs. 32 (25–39), p < 0.05 ; 143B 90.6 (72–100) vs. 39.2 (26–55), p < 0.05 ) were reduced after propofol treatment. Doxorubicin sensitivity was increased after propofol treatment compared with the control group ( p < 0.05 ). Bioinformatic analysis showed significant functional enrichment in ER stress response after propofol treatment. Upregulation of CHOP, p-eIF2α, and XBP1s was detected in MG63 and 143B secondary to propofol treatment. In conclusion, we found that propofol treatment suppressed osteosarcoma proliferation and invasion and had a synergic role with doxorubicin by inducing ER stress. Our findings provided a novel option in osteosarcoma therapy.

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Section: Discussionmentioning

confidence: 99%

“…Endoplasmic reticulum (ER) is involved in the biosynthesis of lipids and proteins, and many factors or drugs could lead to "ER stress," a state induced by the accumulation of misfolded and/or unfolded proteins [20]. ER stressinduced osteosarcoma cell death was extensively reported [21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Propofol Regulates ER Stress to Inhibit Tumour Growth and Sensitize Osteosarcoma to Doxorubicin

Hua

Zhao

et al. 2023

International Journal of Clinical Practice

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“…While in ERS conditions, GRP78 is actively recruited to accumulating misfolded proteins and separates from these three proteins (Fig. 1) [12].…”

Section: Endoplasmic Reticulum Stress (Ers) and Unfolded Protein Resp...mentioning

confidence: 99%

Endoplasmic reticulum stress targeted therapy for breast cancer

Liu

Liang

et al. 2022

Cell Commun Signal

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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.

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“…Three transmembrane proteins, activated transcription factor 6 (ATF6), inositol requirement enzyme 1α (IRE1α), and PrKR-like endoplasmic reticulum kinase (PERK), operate as ER stress sensors in mammalian cells. During ER stress, binding-immunoglobulin protein (BiP; also known as GRP78) dissociates from the sensor ( 2 ). This is an adaptive mechanism that subsequently induces the unfolded protein response (UPR; also known as the ER stress response), which can restore ER homeostasis through various mechanisms, including transcriptional reprogramming, mRNA decay, global translational decay, removal of misfolded proteins through the ER-associated protein degradation system, and recycling of misfolded proteins and cellular materials through the induction of autophagy ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Genomic and clinical features of endoplasmic reticulum stress factor in digestive system pan-cancer studies

Yao

et al. 2023

Front. Oncol.

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IntroductionDigestive system pan-cancer is one of the lethal malignant tumors, which have the propensity for poor prognosis and difficult treatment. Endoplasmic reticulum (ER) stress has served as a pivotal role in the progression of the tumor, while the implication of ER stress on digestive system pan-cancers still needs elucidation, especially from the perspective of clinical outcome and that of genomic features.MethodsFirst, Among the ER STRESS factors from the REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR (113 genes) and HALLMARK_UNFOLDED_PROTEIN_RESPONSE (92 genes) terms, 153 ER STRESS regulators were identified after removing replicates. The somatic mutation data and copy number variation data of gastrointestinal pan-cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Then, we explored the clinical outcome and genetic mutation of ER stress-related differentially expressed genes (DEGs) by multiple bioinformatics analysis. Subsequently, we analyzed the Spearman correlation between the drug sensitivity of 179 gastrointestinal anticancer drugs and the transcriptional expression of 153 ER stress factors in 769 cancer cell lines of the GDSC2 cohort. Next, ssGSEA method was used to quantify the immune cell infiltration scores in the tumor microenvironment, and Spearman correlation was used to calculate the correlation between ER stress scores and immune cell infiltration. Finally, we analyzed the cellular origin of ER stress factor dysregulation.ResultsWe analyzed the genomic changes and clinical outcomes of ER stress factors in different tumors of gastrointestinal pan-cancer. Endoplasmic reticulum stress factor (ER) in digestive tract tumors showed high SNV mutation frequency, less methylation dysregulation and was associated with multiple oncogenic pathways. Endoplasmic reticulum stress factor (ER) is a risk factor for many cancers, but the effect on overall survival in rectal adenocarcinoma is opposite to that in other gastrointestinal tumors. And ER stress factors are highly correlated with drugs that target important pathways.DiscussionBased on the clinical prognosis and genomic analysis of ER stress-related factors in patients with gastrointestinal pan-cancer, this study provides a new direction for further research on gastrointestinal pan-cancer.

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Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity

Cited by 51 publications

References 125 publications

Propofol Regulates ER Stress to Inhibit Tumour Growth and Sensitize Osteosarcoma to Doxorubicin

Propofol Regulates ER Stress to Inhibit Tumour Growth and Sensitize Osteosarcoma to Doxorubicin

Endoplasmic reticulum stress targeted therapy for breast cancer

Genomic and clinical features of endoplasmic reticulum stress factor in digestive system pan-cancer studies

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