IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

Tanabe, Yutaka; Suehara, Yoshiyuki; Kohsaka, Shinji; Hayashi, Takuo; Akaike, Keisuke; Mukaihara, Kenta; Kurihara, Taisei; Kim, Youngji; Okubo, Taketo; Ishii, Midori; Kazuno, Saiko; Kaneko, Kazuo; Saito, Tsuyoshi

doi:10.18632/oncotarget.24467

Cited by 21 publications

(34 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6E). Increased XBP1s/XBP1 ratios were restored to normal levels by additional treatment with either Emapunil or the IRE1␣-XBP1 inhibitor toyocamycin (2hydroxy-1-naphthaldehyde) (Tanabe et al, 2018) (Fig. 6E).…”

Section: Emapunil Mitigates Er Stressmentioning

confidence: 94%

Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism

et al. 2019

View full text Add to dashboard Cite

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Parkinson's disease is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no diseasemodifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18, ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism, and prevents motor dysfunction in female mice treated with the MPTP, as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1␣ (IRE ␣)/X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro-inflammatory toward antiinflammatory microglia activation. Previously, Emapunil was shown to cross the blood-brain barrier and to be safe and well tolerated in a Phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson's disease.

show abstract

Section: Emapunil Mitigates Er Stressmentioning

confidence: 94%

Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Other proteomic studies have recently been carried out for soft tissue sarcomas with specific fusion genes such as EWS/FLI1 (for Ewing sarcomas) and PAX3/FOXO1 (for alveolar rhabdomyosarcoma). These studies have identified numerous proteins; 90 proteins for EWS/FLI1 and 221 proteins for PAX3/FOXO1, despite this SS study have just identified 35 proteins for SS18/SSX [48, 49]. Several functional studies have found that SS18/SSX is not a transcriptional factor but co-activator [1, 9, 43, 26, 44–47].…”

Section: Discussionmentioning

confidence: 99%

Proteomic signatures corresponding to the SS18/SSX fusion gene in synovial sarcoma

et al. 2018

Self Cite

View full text Add to dashboard Cite

Synovial sarcoma (SS) is a malignant soft tissue lesion and most commonly arises in young adults. Chromosomal translocation t(X;18)(p11;q11) results in the formation of SS18/SSX by gene fusion of the SS18 gene on chromosome 18 to either SSX1, SSX2, or SSX4 gene located on chromosome X, which is detected in more than 95% of SSs. Although multiple lines of evidence suggest that the SS18/SSX fusion is the oncogene in this tumor, the protein expression profiles associated with SS18/SSX have yet to be elucidated. In this study, we conducted proteomic studies using SS18/SSX knockdown in three SS cell lines to identify the regulated proteins associated with SS18/SSX in SS. Isobaric tags for relative and absolute quantitation (i-TRAQ) analyses identified approximate 1700–2,000 proteins regulated by the SS18/SSX fusion in each SS cell line. We also analyzed the three profiles to identify proteins that were similarly altered in all 3 cell lines and found 17 consistently upregulated and 18 consistently downregulated proteins, including TAGLN and ACTN4. In addition, network analyses identified several critical pathways including RUNX2 and SMARCA4. RUNX2 and SMARCA4 had the highest ranking in these identified pathways. In addition, we found that expression of TAGLN inhibited cell viability in SS cell lines. Our data suggest that the differentiation and cell growth of SS may be enhanced by the identified proteins induced by SS18/SSX. We believe that the findings obtained in the present functional analyses will help to improve our understanding of the relationship between SS18/SSX and malignant behavior in SS.

show abstract

“…In order to identify the protein signatures regulated by the PAX3-FOXO1 fusion gene product in ARMS and to elucidate the function of PAX3-FOXO1, we performed proteomic analyses using isobaric tags for the relative and absolute quantitation (i-TRAQ) and determined the protein profiles regulated by PAX3-FOXO1 [ 34 , 35 ].…”

Section: Methodsmentioning

confidence: 99%

PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma

et al. 2018

Self Cite

View full text Add to dashboard Cite

To better characterize the oncogenic role of the PAX3-FOXO1 fusion protein in the acquisition of aggressive behavior in ARMS, we employed a proteomic approach using a PAX3-FOXO1 knockdown system in ARMS cell lines. This approach revealed a protein list consisting of 107 consistently upregulated and 114 consistently downregulated proteins that were expected to be regulated by PAX3-FOXO1 fusion protein. Furthermore, we identified 16 upregulated and 17 downregulated critical proteins based on a data-mining analysis. We also evaluated the function of PPP2R1A in ARMS cells. The PPP2R1A expression was upregulated at both the mRNA and protein levels by PAX3-FOXO1 silencing. The silencing of PPP2R1A significantly increased the cell growth of all four ARMS cells, suggesting that PPP2R1A still has a tumor suppressive function in ARMS cells; however, the native expression of PPP2R1A was low in the presence of PAX3-FOXO1. In addition, the activation of PP2A—part of which was encoded by PPP2R1A—by FTY720 treatment in ARMS cell lines inhibited cell growth. On the human phospho-kinase array analysis of 46 specific Ser/Thr or Tyr phosphorylation sites on 39 selected proteins, eNOS, AKT1/2/3, RSK1/2/3 and STAT3 phosphorylation were decreased by FTY-720 treatment. These findings suggest that PPP2R1A is a negatively regulated by PAX3-FOXO1 in ARMS. The activation of PP2A—probably in combination with kinase inhibitors—may represent a therapeutic target in ARMS. We believe that the protein expression profile associated with PAX3-FOXO1 would be valuable for discovering new therapeutic targets in ARMS.

show abstract

IRE1α-XBP1 inhibitors exerted anti-tumor activities in Ewing’s sarcoma

Cited by 21 publications

References 46 publications

Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism

Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism

Proteomic signatures corresponding to the SS18/SSX fusion gene in synovial sarcoma

PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma

Contact Info

Product

Resources

About