Dynamics and clustering of IRE1α during ER stress

Rainbolt, T. Kelly; Frydman, Judith

doi:10.1073/pnas.1921799117

Cited by 9 publications

(7 citation statements)

References 22 publications

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“…Since cytoskeletal manipulation proved effective in tuning the ER response to DON-3-Sulf, CQ, and rapamycin, additional experiments were performed to explore the connection with IRE1 (inositol-requiring protein 1). IRE1 serves as ER stress signal and activator of the unfolded protein response (UPR, ( Adams et al, 2019 ; Rainbolt and Frydman, 2020 ). Since in the ER patterning we observed rearrangement from the cell periphery to the nuclear/perinuclear region, signal intensity was quantified in proximity to the nuclear area, as well as in the cytoplasmic compartment, taking cell nuclei (DAPI) and actin as references.…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic Reticulum Adaptation and Autophagic Competence Shape Response to Fluid Shear Stress in T24 Bladder Cancer Cells

et al. 2021

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Accumulation of xenobiotics and waste metabolites in the urinary bladder is constantly accompanied by shear stress originating from the movement of the luminal fluids. Hence, both chemical and physical cues constantly modulate the cellular response in health and disease. In line, bladder cells have to maintain elevated mechanosensory competence together with chemical stress response adaptation potential. However, much of the molecular mechanisms sustaining this plasticity is currently unknown. Taking this as a starting point, we investigated the response of T24 urinary bladder cancer cells to shear stress comparing morphology to functional performance. T24 cells responded to the shear stress protocol (flow speed of 0.03 ml/min, 3 h) by significantly their its surface area. When exposed to deoxynivalenol-3-sulfate (DON-3-Sulf), bladder cells increased this response in a concentration-dependent manner (0.1–1 µM). DON-3-Sulf is a urinary metabolite of a very common food contaminant mycotoxin (deoxynivalenol, DON) and was already described to enhance proliferation of cancer cells. Incubation with DON-3-Sulf also caused the enlargement of the endoplasmic reticulum (ER), decreased the lysosomal movement, and increased the formation of actin stress fibers. Similar remodeling of the endoplasmic reticulum and area spread after shear stress were observed upon incubation with the autophagy activator rapamycin (1–100 nM). Performance of experiments in the presence of chloroquine (chloroquine, 30 μM) further contributed to shed light on the mechanistic link between adaptation to the biomechanical stimulation and ER stress response. At the molecular level, we observed that ER reshaping was linked to actin organization, with the two components mutually regulating each other. Indeed, we identified in the ER stress–cytoskeletal rearrangement an important axis defining the physical/chemical response potential of bladder cells and created a workflow for further investigation of urinary metabolites, food constituents, and contaminants, as well as for pharmacological profiling.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic Reticulum Adaptation and Autophagic Competence Shape Response to Fluid Shear Stress in T24 Bladder Cancer Cells

et al. 2021

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“…The latter is generally catalyzed by eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2, best known as PKR) and EIF2AK3 (best known as PERK), which are particularly sensitive to the accumulation of unfolded proteins within the ER 149 . Intriguingly, the other reticular arms of the ISR such as the splicing of X-box binding protein 1 (XBP1) 150 , as well as the derepression of activating transcription factor 4 (ATF4) and ATF6 151,152 are not mechanistically linked to the immunogenicity of dying cancer cells, meaning that solely the phosphorylation of eIF2α constitutes a pathognomonic feature of ICD 149,153 . The ICD-associated phosphorylation of eIF2α can be detected by immunoblotting, flow cytometry, and immunofluorescence microscopy based on phosphoneoepitope-specific antibodies [154][155][156][157][158] , with the latter two approaches offering the scalability that is needed for HCS applications.…”

Section: Monitoring Calr Hsps and The Isrmentioning

confidence: 99%

Detection of immunogenic cell death and its relevance for cancer therapy

et al. 2020

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Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.

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“…Following translation, the XBP1-spliced event causes a frameshift in the mRNA, making the transcription factor XBP1 active and stable. Subsequently, as part of a transcriptional program to solve the protein misfolding in the ER, the XBP1 transcription factor determines the expressions of lipid biosynthesis linked genes and ER chaperones [ 72 ]. In higher eukaryotes, IRE1α activation triggers the downregulated translation of ER-targeted proteins via the direct degradation of ER-localized mRNAs in a process known as RIDD.…”

Section: Canonical Pathway Regulates Er-stress Responsementioning

confidence: 99%

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy

Alam

Kabir

Kim

et al. 2022

Cells

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Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment.

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Dynamics and clustering of IRE1α during ER stress

Cited by 9 publications

References 22 publications

Endoplasmic Reticulum Adaptation and Autophagic Competence Shape Response to Fluid Shear Stress in T24 Bladder Cancer Cells

Endoplasmic Reticulum Adaptation and Autophagic Competence Shape Response to Fluid Shear Stress in T24 Bladder Cancer Cells

Detection of immunogenic cell death and its relevance for cancer therapy

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy

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