Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP

Cao, Yang; He, Yayi; Yang, Litao; Luan, Zhou

doi:10.3892/or.2020.7856

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…To test the effects of these inhibitors in vivo , we treated MCF7 xenografts with the eIF4A inhibitor, CR-31-B 63 , fulvestrant or the combination. To determine if estrogen levels affected the anti-tumor efficacy of this combination, we used mice implanted with either low (0.18mg) or high (0.72mg) estrogen pellets (Figure 3D-G).…”

Section: Resultsmentioning

confidence: 99%

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eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Boyer,

Sharma,

Dorso

et al. 2024

Preprint

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The majority of human breast cancers are dependent on hormone stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap independent and mTOR inhibitor insensitive, but dependent on 5'UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short lived targets of ER such as cyclin D1 and other components of the cyclin D CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant, an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

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Section: Resultsmentioning

confidence: 99%

“…Many transcripts have been described as sensitive to eIF4A inhibition, and eIF4A inhibitors can block the growth of various cancer models 52,[58][59][60][61][62][63] . We therefore sought to determine the global protein changes that occur in ER+ breast cancer models after eIF4A inhibition.…”

Section: Eif4a Regulates Er Activity and Cell Growthmentioning

confidence: 99%

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

Boyer,

Sharma,

Dorso

et al. 2024

Preprint

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“…Brefeldin A has been reported to markedly inhibit proliferation and induce autophagic cell death via the Akt/ mTOR and ERK pathways when encapsulated in mixed nanomicelles (45). CR-1-31B, an inhibitor of eukaryotic translation initiation factor 4A, has been found to significantly reduce the growth and initiate the apoptosis of gallbladder cancer cells (46). In addition, one article reported that the Src/FAK pathway inhibitor KX2-391 significantly increased the sensitivity of HepG2/doxorubicin cells to doxorubicin in HCC (47).…”

Section: Discussionmentioning

confidence: 99%

A Novel Artificial Neural Network Prognostic Model Based on a Cancer-Associated Fibroblast Activation Score System in Hepatocellular Carcinoma

et al. 2022

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IntroductionHepatocellular carcinoma (HCC) ranks fourth as the most common cause of cancer-related death. It is vital to identify the mechanism of progression and predict the prognosis for patients with HCC. Previous studies have found that cancer-associated fibroblasts (CAFs) promote tumor proliferation and immune exclusion. However, the information about CAF-related genes is still elusive.MethodsThe data were obtained from The Cancer Genome Atlas, International Cancer Genome Consortium, and Gene Expression Omnibus databases. On the basis of single-cell transcriptome and ligand–receptor interaction analysis, CAF-related genes were selected. By performing Cox regression and random forest, we filtered 12 CAF-related prognostic genes for the construction of the ANN model based on the CAF activation score (CAS). Then, functional, immune, mutational, and clinical analyses were performed.ResultsWe constructed a novel ANN prognostic model based on 12 CAF-related prognostic genes. Cancer-related pathways were enriched, and higher activated cell crosstalk was identified in high-CAS samples. High immune activity was observed in high-CAS samples. We detected three differentially mutated genes (NBEA, RYR2, and FRAS1) between high- and low-CAS samples. In clinical analyses, we constructed a nomogram to predict the prognosis of patients with HCC. 5-Fluorouracil had higher sensitivity in high-CAS samples than in low-CAS samples. Moreover, some small-molecule drugs and the immune response were predicted.ConclusionWe constructed a novel ANN model based on CAF-related genes. We revealed information about the ANN model through functional, mutational, immune, and clinical analyses.

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“…These small molecules have been found to play anti-tumor roles in several cancers. For example, CR-1-31B, a synthetic rocaglate and a potent eIF4A inhibitor, significantly reduced the growth and apoptosis of neuroblastoma and gallbladder tumor cells ( 43 , 44 ). PHA-793887, a novel and potent inhibitor of CDK, showed promising efficacy in the human ovarian A2780, colon HCT-116, and pancreatic BX-PC3 cancer xenograft models ( 45 , 46 ).…”

Section: Methodsmentioning

confidence: 99%

Identify the immune characteristics and immunotherapy value of CD93 in the pan-cancer based on the public data sets

Guo

Zhang²,

Tian³

et al. 2022

Front. Immunol.

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CD93 is a transmembrane receptor that is mainly expressed on endothelial cells. A recent study found that upregulated CD93 in tumor vessels is essential for tumor angiogenesis in several cancers. However, the underlying mechanisms are largely unexplored. Our present research systematically analyzed the characteristics of CD93 in tumor immunotherapy among 33 cancers. CD93 levels and co-expression of CD93 on cancer and stromal cells were detected using public databases and multiple immunofluorescence staining. The Kaplan-Meier (KM) analysis identified the predictive role of CD93 in these cancer types. The survival differences between CD93 mutants and WT, CNV groups, and methylation were also investigated. The immune landscape of CD93 in the tumor microenvironment was analyzed using the SangerBox, TIMER 2.0, and single-cell sequencing. The immunotherapy value of CD93 was predicted through public databases. CD93 mRNA and protein levels differed significantly between cancer samples and adjacent control tissues in multiply cancer types. CD93 mRNA expression associated with patient prognosis in many cancers. The correlation of CD93 levels with mutational status of other gene in these cancers was also analyzed. CD93 levels significantly positively related to three scores (immune, stromal, and extimate), immune infiltrates, immune checkpoints, and neoantigen expression.. Additionally, single-cell sequencing revealed that CD93 is predominantly co-expressed on tumor and stromal cells, such as endothelial cells, cancer-associated fibroblasts (CAFs), neutrophils, T cells, macrophages, M1 and M2 macrophages. Several immune-related signaling pathways were enriched based on CD93 expression, including immune cells activation and migration, focal adhesion, leukocyte transendothelial migration, oxidative phosphorylation, and complement. Multiple immunofluorescence staining displayed the relationship between CD93 expression and CD8, CD68, and CD163 in these cancers. Finally, the treatment response of CD93 in many immunotherapy cohorts and sensitive small molecules was predicted from the public datasets. CD93 expression is closely associated with clinical prognosis and immune infiltrates in a variety of tumors. Targeting CD93-related signaling pathways in the tumor microenvironment may be a novel therapeutic strategy for tumor immunotherapy.

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Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP

Cited by 9 publications

References 28 publications

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer

A Novel Artificial Neural Network Prognostic Model Based on a Cancer-Associated Fibroblast Activation Score System in Hepatocellular Carcinoma

Identify the immune characteristics and immunotherapy value of CD93 in the pan-cancer based on the public data sets

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