Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

Kitakaze, Keisuke; Taniuchi, Shusuke; Kawano, Eri; Hamada, Yoshimasa; Miyake, Masato; Oyadomari, Miho; Kojima, Hirotatsu; Kosako, Hidetaka; Kuribara, Tomoko; Yoshida, Suguru; Hosoya, Takamitsu; Oyadomari, Seiichi

doi:10.7554/elife.43302

Cited by 23 publications

(16 citation statements)

References 51 publications

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“… 38 Specifically, the accumulation of misfolded proteins in the ER results in diffuse cytoplasmic staining, whereas an increase in polyubiquitinated proteins in the proteasome leads to discrete punctate staining of perinuclear structures. 39 As expected, the tPF@PCM + laser group exhibited the brightest fluorescence with both staining patterns of aggregated proteins. In contrast, cells treated with tF@PCM and tF@PCM + laser exhibited only diffuse cytoplasmic staining, whereas the tP@PCM and tP@PCM + laser groups exhibited punctate red fluorescence ( Figure 4C ).…”

Section: Resultssupporting

confidence: 72%

Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy

Cai¹,

Hou²,

Zhang³

et al. 2021

IJN

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Background Recently, nanocatalyst-induced endoplasmic reticulum (ER) stress for cancer therapy has been attracting considerable attention. However, cancer cells are often able to overcome ER stress-induced death by activating the unfolded protein response (UPR), making nanocatalytic monotherapy a poor defense against cancer progression. Purpose In this study, to improve the nanocatalytic treatment efficacy, a phase change material (PCM) was used to encapsulate the upstream ER stress initiator, iron oxide nanoparticles (Fe 3 O 4 NPs), and the downstream UPR modulator, PR-619. Subsequently, the tumor-homing peptide tLyP-1 was coupled to it to form tLyP-1/PR-619/Fe 3 O 4 @PCM (tPF@PCM) theranostic platform. Materials and Methods tPF@PCM was synthesized using nanoprecipitation and resolidification methods followed by the EDC/NHS cross-linking method. The targeting capacity of tPF@PCM was evaluated in vitro and in vivo using flow cytometry and magnetic resonance imaging, respectively. The therapeutic efficacy of tPF@PCM was investigated in a renal cell carcinoma mouse model. Moreover, we explored the synergistic anti-tumor mechanism by examining the intracellular reactive oxygen species (ROS), aggregated proteins, ER stress response levels, and type of cell death. Results tPF@PCM had excellent tumor-targeting properties and exhibited satisfactory photothermal-enhanced tumor inhibition efficacy both in vitro and in vivo. Specifically, the phase transition temperature (45 °C) maintained using 808 nm laser irradiation significantly increased the release and catalytic activity of the peroxidase mimic Fe 3 O 4 NPs. This strongly catalyzed the generation of hydroxyl radicals (•OH) via the Fenton reaction in the acidic tumor microenvironment. The redox imbalance subsequently resulted in an increase in the level of damaged proteins in the ER and initiated ER stress. Moreover, the pan-deubiquitinase inhibitor PR-619 blocked the “adaptive” UPR-mediated degradation of these damaged proteins, exacerbating the ER burden. Consequently, irremediable ER stress activated the “terminal” UPR, leading to apoptosis in cancer cells. Conclusion This ER stress-exacerbating strategy effectively suppresses tumorigenesis, offering novel directions for advances in the treatment of conventional therapy-resistant cancers.

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Section: Resultssupporting

confidence: 72%

Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy

Cai¹,

Hou²,

Zhang³

et al. 2021

IJN

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“…The use of chemical chaperones is a promising approach to alleviate ER stress in a range of diseases. The antidiabetic compound azoramide and BIP/GRP78 inducer X (BiX) were found to improve ER protein-folding capability in multiple systems [ 163 , 164 ]. In addition, 4-Phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA) have shown therapeutic benefits for a wide variety of diseases, such as AD, ALS and diabetes [ 165 , 166 ].…”

Section: Therapeutic Approaches: Chemical Compounds Targeting the mentioning

confidence: 99%

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

Ghemrawi

Khair

2020

IJMS

215

136

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The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation.

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“…Recently, 2-phenylimidazole[2,1-b]benzothiazole derivatives (IBTs) were found to ameliorate protein aggregation under ER stress at micromolar concentrations. 29 The effective concentrations of GIF-0854-r and -0856-r are similar to those of IBTs. Another advantage of GIF-0854-r and -0856-r is that they prevent both ER stress and oxytosis/ferroptosis, a form of regulated cell death distinct from apoptosis, necrosis, and autophagy.…”

Section: ■ Introductionmentioning

confidence: 78%

Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones

Hasegawa

Motoyama

Hamamoto

et al. 2022

ACS Chem. Neurosci.

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Endoplasmic reticulum (ER) stress and oxidative stress lead to protein misfolding, and the resulting accumulation of protein aggregates is often associated with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion disease. Small molecules preventing these pathogenic processes may be effective interventions for such neurodegenerative disorders. In this paper, we identify several novel oxindole compounds that can prevent ER stress-and oxidative stress-induced cell death. Among them, derivatives of the lead compound GIF-0726-r in which a hydrogen atom at the oxindole ring 5 position is substituted with a methyl (GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) group potently suppressed global ER stress. Furthermore, GIF-0854-r and -0856-r prevented protein aggregate accumulation in vitro and in cultured hippocampal HT22 neuronal cells, indicating that these two compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamateinduced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-r and -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying the molecular mechanisms of ER and oxidative stress.

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Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

Cited by 23 publications

References 51 publications

Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy

Dual Targeting of Endoplasmic Reticulum by Redox-Deubiquitination Regulation for Cancer Therapy

Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones

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