Target Eukaryotic Translation Initiation Factor Research Articles

52 Bricilib - a new strategy for the treatment of psoriasis targeting eukaryotic translation initiation factor 4E

52 Bricilib - a new strategy for the treatment of psoriasis targeting eukaryotic translation initiation factor 4E

Hsa_circ_0102899 promotes epithelial-mesenchymal transition in non-small cell lung cancer.

The significance of circular RNAs (circRNAs) has been identified in the progression of non-small cell lung cancer (NSCLC). Consistently, our study probed the functional actions of hsa_circ_0102899 (circ_0102899) in NSCLC cells. circ_0102899 expression was checked in NSCLC tissues, as well as its correlation with clinical characteristics of patients, Using A459 cells, transfection to alter gene expression was performed, thus measuring the changes of proliferation, apoptosis, migration, and apoptosis, as well as epithelial-mesenchymal transition (EMT)-related proteins. circ_0102899's effects in vivo were validated by tumor xenograft assay. Finally, the regulatory mechanism of circ_0102899 was investigated. circ_0102899 indicated a high-expression level in NSCLC tissues which was associated with NSCLC tumor characteristics. Functionally, circ_0102899 knockdown not only inhibited the growth and EMT process of NSCLC cells, but also inhibited tumor formation in vivo. In terms of the regulatory mechanism, circ_0102899 had a binding to miR-885-5p to target eukaryotic translation initiation factor 4γ2 (EIF4G2). circ_0102899 mediated miR-885-5/EIF4G2 axis to accelerate the process of cell malignant behavior in NSCLC. circ_0102899 promotes EMT and metastasis in NSCLC by regulating the miR-885-5p/EIF4G2 axis.

SHCBP1 contributes to the proliferation and self‑renewal of cervical cancer cells and activation of the NF‑κB signaling pathway through EIF5A.

Cervical cancer (CC) is the most common human papillomavirus-related disease. Continuous activation of the NF-κB signaling pathway has been observed in CC. SHC binding and spindle associated 1 (SHCBP1) contributes to tumorigenesis and activation of the NF-κB pathway in multiple cancer types, while its function in CC remains unclear. In the present study, three Gene Expression Omnibus datasets were used to identify differentially expressed genes (DEGs) in CC. Loss- and gain-of-function experiments were performed using stable SHCBP1-silenced and SHCBP1-overexpressing CC cells. To further explore the molecular mechanism of SHCBP1 in CC, small interfering RNA targeting eukaryotic translation initiation factor 5A (EIF5A) was transfected into stable SHCBP1-overexpressing CC cells. The results demonstrated that SHCBP1 was an upregulated DEG in CC tissues compared with healthy control cervical tissues. Functional experiments revealed the pro-proliferative and pro-stemness role of SHCBP1 in CC cells (CaSki and SiHa cells), in vitro. Furthermore, the NF-κB signaling pathway in CC cells was activated by SHCBP1. Increases in cell proliferation, stemness and activation of NF-κB, induced by SHCBP1 overexpression in CC cells, were reversed by EIF5A knockdown. Taken together, the results indicated that SHCBP1 serves an important role in regulation of CC cell proliferation, self-renewal and activation of NF-κB via EIF5A. The present study demonstrated a potential molecular mechanism underlying the progression of CC.

Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax

BackgroundThe BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL).MethodsWe tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex.ResultsTreatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis.ConclusionsOur data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.

A miRNA- and mRNA-seq-Based Feature Selection Approach for Kidney Cancer Biomakers.

Microarray data sets have been used for predicting cancer biomarkers. Yet, replication of the prediction has not been fully satisfied. Recently, new data sets called deep sequencing data sets have been generated, with an advantage of less noise in computational analysis. In this study, we analyzed the kidney miRNA and mRNA sequence data sets for predicting cancer markers using 5 different statistical feature selection methods. In the results, we obtained 3 mRNA- and 27 miRNA-based cancer biomarkers to compare with the normal samples. In addition, we clustered the kidney cancer subtypes using a nonnegative matrix factorization method and obtained significant results of survival analysis from the 2 separate groups including miRNA-342 and its target eukaryotic translation initiation factor 5A (EIF5A).

MTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β1-induced collagen biosynthesis.

The differentiation of fibroblasts into a transient population of highly activated, extracellular matrix (ECM)-producing myofibroblasts at sites of tissue injury is critical for normal tissue repair. Excessive myofibroblast accumulation and persistence, often as a result of a failure to undergo apoptosis when tissue repair is complete, lead to pathological fibrosis and are also features of the stromal response in cancer. Myofibroblast differentiation is accompanied by changes in cellular metabolism, including increased glycolysis, to meet the biosynthetic demands of enhanced ECM production. Here, we showed that transforming growth factor-β1 (TGF-β1), the key pro-fibrotic cytokine implicated in multiple fibrotic conditions, increased the production of activating transcription factor 4 (ATF4), the transcriptional master regulator of amino acid metabolism, to supply glucose-derived glycine to meet the amino acid requirements associated with enhanced collagen production in response to myofibroblast differentiation. We further delineated the signaling pathways involved and showed that TGF-β1-induced ATF4 production depended on cooperation between canonical TGF-β1 signaling through Smad3 and activation of mechanistic target of rapamycin complex 1 (mTORC1) and its downstream target eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). ATF4, in turn, promoted the transcription of genes encoding enzymes of the de novo serine-glycine biosynthetic pathway and glucose transporter 1 (GLUT1). Our findings suggest that targeting the TGF-β1-mTORC1-ATF4 axis may represent a novel therapeutic strategy for interfering with myofibroblast function in fibrosis and potentially in other conditions, including cancer.

Suppression of oncogenic protein translation via targeting eukaryotic translation initiation factor 4E overcomes chemo-resistance in nasopharyngeal carcinoma

Resistance to adjuvant chemotherapy remains therapeutic challenge in nasopharyngeal carcinoma (NPC). In this work, we demonstrate that targeting eukaryotic translation initiation factor 4E (eIF4E) is a potential sensitizing strategy to overcome chemoresistance in NPC. We observe the aberrant activation of eIF4E and translational upregulation of eIF4E-regulated oncogenes in NPC cell after pro-longed exposure of cisplatin. Functional analysis demonstrates that eIF4E depletion effectively inhibits proliferation and induces apoptosis in cisplatin-resistant NPC cells. Consistently, eIF4E knockdown significantly enhances cisplatin efficacy in cisplatin-sensitive cells. We identify eIF4E as a therapeutically actionable targets by showing that ribavirin, an anti-viral drug, phenocopies the effects of eIF4E knockdown in NPC. We further demonstrate that ribavirin acts on chemoresistant NPC cells through suppressing eIF4E activity and oncogenic protein translation. Using two independent NPC xenograft mouse models, we show that ribavirin not only is effective in inhibiting chemoresistant NPC growth but also significantly augments the inhibitory effects of cisplatin efficacy in vivo without causing significant toxicity in mice. Taken together, our work shows an activation of eIF4E-mediated growth and survival mechanisms in response to chemotherapy and suggests that inhibition of eIF4E activity represents an attractive sensitizing strategy for NPC treatment. Our findings also suggest that ribavirin is a useful addition to the treatment armamentarium for NPC.

Ingestion of frying fat leads to activation of the endoplasmic reticulum stress-induced unfolded protein response in the duodenal mucosa of pigs.

Ingestion of oxidized fats (OF) causes activation of stress signaling pathways such as nuclear factor-erythroid 2-related factor 2 (Nrf2) in the intestine. Activation of this pathway is mediated by ER stress-induced unfolded protein response (UPR). Herein, we hypothesized that ingestion of OF causes ER stress-induced UPR in duodenal mucosa of pigs. Six-wk-old cross-bred pigs received either a control diet with fresh fat or a diet with OF for 29 days. Pigs fed OF exhibited increased phosphorylation of the ER stress downstream target eukaryotic translation initiation factor 2α and induction of several genes involved in ER stress-induced UPR and Nrf2 target genes in duodenal mucosa. No signs of an impaired intestinal barrier function or a systemic inflammatory response could be found in pigs fed OF. Activation of ER stress-induced UPR by OF in the duodenal mucosa in pigs might be interpreted as a cytoprotective response to stress factors associated with ingestion of OF. Given the similarities between pigs and humans with respect to digestive physiology, it is possible that regular ingestion of fried foods containing OF activates the ER stress-induced UPR also in the intestinal mucosa of humans.

The PERK-eIF2α signaling pathway is involved in TCDD-induced ER stress in PC12 cells

Studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces apoptotic cell death in neuronal cells. However, whether this is the result of endoplasmic reticulum (ER) stress-mediated apoptosis remains unknown. In this study, we determined whether ER stress plays a role in the TCDD-induced apoptosis of pheochromocytoma (PC12) cells and primary neurons. PC12 cells were exposed to different TCDD concentrations (1, 10, 100, 200, or 500nM) for varying lengths of time (1, 3, 6, 12, or 24h). TCDD concentrations much higher than 10nM (100, 200, or 500nM) markedly increased glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) levels, which are hallmarks of ER stress. We also evaluated the effects of TCDD on ER morphology in PC12 cells and primary neurons that were treated with different TCDD concentrations (1, 10, 50, or 200nM) for 24h. Ultrastructural ER alterations were observed with transmission electron microscopy in PC12 cells and primary neurons treated with high concentrations of TCDD. Furthermore, TCDD-induced ER stress significantly promoted the activation of the PKR-like ER kinase (PERK), a sensor for the unfolded protein response (UPR), and its downstream target eukaryotic translation initiation factor 2 α (eIF2α); in contrast, TCDD did not appear to affect inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6), two other UPR sensors. Importantly, TCDD significantly inhibited eIF2α phosphorylation and triggered apoptosis in PC12 cells after 6–24h of treatment. Salubrinal, which activates the PERK-eIF2α pathway, significantly enhanced eIF2α phosphorylation in PC12 cells and attenuated the TCDD-induced cell death. In contrast, knocking down eIF2α using small interfering RNA markedly enhanced TCDD-induced cell death. Together, these results indicate that the PERK-eIF2α pathway plays an important role in TCDD-induced ER stress and apoptosis in PC12 cells.

Targeting Eukaryotic Translation Initiation Factor 4E (eIF4E) in Cancer

Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action.

Mst1, RanBP2 and eIF4G are new markers for in vivo PI3K activation in murine and human prostate

Phosphatidylinositol 3-kinases (PI3Ks) constitute important regulators of signaling pathways. The PIK3CA gene encoding the p110-alpha catalytic subunit represents one of the highly mutated oncogenes identified in human cancer. Here, we report new markers for in vivo PI3K activation in prostate. To that end, we used a transgenic mouse line, which expresses a constitutively active p110-alpha subunit in the epithelial cells of the prostate. The activity of the PI3K pathway in the prostate was proven by assessing the phosphorylation of the PI3K direct target AKT1 and of the mTOR target eukaryotic translation initiation factor 4G (eIF4G). To establish also transcriptional ('late') targets of the PI3K pathway, we tested two genes, Mst1 and RanBP2, which we recently described as transcriptional targets of the growth factor platelet-derived growth factor-beta. We show that the levels of both proteins are elevated in transgenic animals. Additionally, we describe that the phosphorylation of AKT and eIF4G, as well as the elevation of the Mst1 and RanBP2 protein levels, can be inhibited in vivo in transgenic animals by the PI3K inhibitor LY294002. Finally, we performed human tissue microarray experiments with the four markers. Since they define overlapping but not identical subsets of the tested tissue panel, a combination of all four markers might lead to a more accurate diagnosis of the status of the PI3K-signaling cascade in cancer patients.

The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin alpha(V)beta(3) and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell-specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin alpha(V)beta(3)-expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas alpha(V)beta(3)-expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA-mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an alpha(V)beta(3)-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the alpha(V)beta(3)-deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted alpha(V)beta(3)-expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/mTOR activation.