SAR Study of a Novel Triene-ansamycin Group Compound, Quinotrierixin, and Related Compounds, as Inhibitors of ER Stress-induced XBP1 Activation

Kawamura, Tatsuro; Tashiro, Etsu; Yamamoto, Kohta; Shindo, Kazutoshi; Imoto, Masaya

doi:10.1038/ja.2008.43

Cited by 25 publications

(6 citation statements)

References 18 publications

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“…24, 30 In the course of further screening for an inhibitor of ER stress-induced XBP1 activation, we isolated toyocamycin 25 from a culture broth of an Actinomycete strain (Figure 1a). As shown in Figure 1b, 0.1 μℳ thapsigargin, an inhibitor of the ER calcium pump (SERCA), elevated XBP1-luciferase activity about 2.5-fold more than the control in HeLa/XBP1-luc cells.…”

Section: Resultsmentioning

confidence: 99%

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing

Tashiro

Oikawa

et al. 2012

Blood Cancer Journal

154

125

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The IRE1α-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy.

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Section: Resultsmentioning

confidence: 99%

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing

Tashiro

Oikawa

et al. 2012

Blood Cancer Journal

154

125

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“…We have also reported that novel trieneansamycin group compounds, quinotrierixin and trierixin, inhibited ER stress-induced XBP1 mRNA splicing in HeLa cells. [15][16][17][18] In this study, we found that quinotrierixin inhibited protein synthesis. Moreover, we investigated the relationship between quinotrierixin-inhibited ER stress-induced XBP1 mRNA splicing and protein synthesis.…”

mentioning

confidence: 75%

“…Quinotrierixin, trierixin, and trienomycin A were prepared as described in our previous reports. 15,17) Cytotrienin A was kindly provided by Dr. H. Osada (RIKEN, Japan). Cycloheximide, anisomycin, and puromycin were purchased from Sigma (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Quinotrierixin Inhibited ER Stress-Induced XBP1 mRNA Splicing through Inhibition of Protein Synthesis

Yamamoto

Tashiro

Imoto

2011

Bioscience, Biotechnology, and Biochemistry

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“…It was first identified by the Tashiro group in 2007, as a specific inhibitor of ER stress-induced XBP1 mRNA splicing (Kawamura et al, 2008a). QT dose-dependently inhibits TG-induced XBP1 splicing in Hela cells with an IC50 of 0.067 μM (Kawamura et al, 2008b). However, a later study from the same group demonstrated that QT inhibits the protein production of UPR genes, including the 78-kDa glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), ERdj4 and P58ipk (Yamamoto et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium

et al. 2018

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Normal function of the retinal pigment epithelium (RPE) is essential for maintaining the structural integrity of retinal photoreceptors and the visual process. Sustained oxidative damage of the RPE due to aging and other risk factors contributes to the development of age-related macular degeneration (AMD). The transcription factor NF-E2-related factor 2 (Nrf2) is a central regulator of cellular antioxidant and detoxification responses. Enhancing Nrf2 function protects RPE cells from oxidation-related apoptosis and cell death. Previously, we demonstrated that Nrf2 activation can be induced by endoplasmic reticulum (ER) stress; however, the mechanisms are not fully understood. In the present study, we examined the role of X box-binding protein 1 (XBP1), an ER stress-inducible transcription factor, in regulation of Nrf2 in the RPE. We found that RPE-specific XBP1 conditional knockout (cKO) mice exhibit a significant reduction in Nrf2 mRNA and protein levels, along with decreased expression of major Nrf2 target genes, in the RPE/choroid complex. Using primary RPE cells isolated from XBP1 cKO mice and human ARPE-19 cell line, we confirmed that loss of XBP1 gene or pharmacological inhibition of XBP1 splicing drastically reduces Nrf2 levels in the RPE. Conversely, overexpression of spliced XBP1 results in a modest but significant increase in cytosolic and nuclear Nrf2 protein levels without affecting the transcription of Nrf2 gene. Moreover, induction of ER stress by tunicamycin and thapsigargin markedly increases Nrf2 expression, which is abolished in cells pretreated with XBP1 splicing inhibitors 4μ8C and quinotrierixin. Mechanistic studies indicate that quinotrierixin reduces Nrf2 expression likely through inhibition of protein translation. Finally, we demonstrate that overexpression of Nrf2 protected RPE cells against oxidative injury but appeared to be insufficient to rescue from XBP1 deficiency-induced cell death. Taken together, our results indicate that XBP1 modulates Nrf2 activity in RPE cells and that XBP1 deficiency contributes to oxidative injury of the RPE.

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SAR Study of a Novel Triene-ansamycin Group Compound, Quinotrierixin, and Related Compounds, as Inhibitors of ER Stress-induced XBP1 Activation

Cited by 25 publications

References 18 publications

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing

Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing

Quinotrierixin Inhibited ER Stress-Induced XBP1 mRNA Splicing through Inhibition of Protein Synthesis

Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium

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