scholarly journals PRP4K is a haploinsufficient tumour suppressor negatively regulated during epithelial-to-mesenchymal transition

2020 ◽  
Author(s):  
Livia E. Clarke ◽  
Carter Van Iderstine ◽  
Sabateeshan Mathavarajah ◽  
Amit Bera ◽  
Moamen Bydoun ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Essential Gene ◽  
Protein Translation ◽  
Mammary Epithelial ◽  
Tumour Suppressor ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Tumour Suppressor Genes ◽  
Mesenchymal Transition ◽  
Cellular Phenotypes

ABSTRACTReduced expression of haploinsufficient tumour suppressor genes is sufficient to alter cellular phenotypes towards carcinogenesis without complete loss of gene expression. As an essential gene, complete expression loss of pre-mRNA processing factor 4 kinase (PRP4K, also known as PRPF4B) is lethal. However, we demonstrate here that reduction of PRP4K levels by small interfering RNA in the mammary epithelial cell lines HMLE and MCF10A can induce partial epithelial-to-mesenchymal transition (EMT) marked by the retention of epithelial markers such as Zo-1 and E-cadherin, and upregulation of mesenchymal markers such as fibronectin and Zeb1. This partial EMT phenotype in non-transformed PRP4K-depleted cells is associated with greater invasive potential in 3D transwell assays, but either reduces or has no effect on 2D migration examined by scratch assay. This is in contrast to depletion of PRP4K in transformed triple-negative MDA-MB-231 breast cancer cells, which results in enhanced migration in 2D and invasion in 3D. Induction of EMT, using EMT-inducing media containing WNT-5a and TGF-β1 or depletion of eukaryotic translation initiation factor 3e (eIF3e) by shRNA, results in marked reduction of PRP4K expression. EMT induced by eIF3e depletion does not affect the transcription of PRP4K mRNA or turn-over of PRP4K protein, but rather reduces its protein translation. Finally, reduced PRP4K levels after eIF3e depletion correlated with increased YAP activity and nuclear localization, the latter being reversed by overexpression of exogenous PRP4K. Together, these data indicate that PRP4K is a haploinsufficient tumour suppressor negatively regulated by EMT, and that when depleted can induce partial EMT and increased cell invasion.

scholarly journals High intratumoral expression of eIF4A1 promotes epithelial-to-mesenchymal transition and predicts unfavorable prognosis in gastric cancer

2020 ◽  
Vol 52 (3) ◽  
pp. 310-319 ◽  
Author(s):  
Chanchan Gao ◽  
Xinyin Guo ◽  
Anwei Xue ◽  
Yuanyuan Ruan ◽  
Hongshan Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Translation Initiation ◽  
Epithelial To Mesenchymal Transition ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Migration And Invasion ◽  
Gastric Cancer Cells ◽  
Mesenchymal Transition

Abstract Gastric cancer is an important health problem, being the fifth most common cancer and the third leading cause of cancer-related death worldwide. Aberrant protein translation contributes to the oncogenesis and development of cancers, and upregulation of translation initiation factor eIF4A1 has been observed in several kinds of malignancies. However, the role of eIF4A1 in gastric cancer progression remains unclear. In this study, we found that the expression of eIF4A1, a component of translation initiation complex, was increased in gastric cancer. High expression of eIF4A1 was positively associated with poor tumor differentiation, late T stage, lymph node metastasis, advanced TNM stage, and poor prognosis in patients with gastric cancer. Overexpression of eIF4A1 promoted the migration and invasion of gastric cancer cells in vitro and enhanced tumor metastasis in nude mice model. Mechanism studies revealed that eIF4A1 induced epithelial-to-mesenchymal transition (EMT) of gastric cancer cells through driving the translation of SNAI1 mRNA. Together, these findings indicate that eIF4A1 promotes EMT and metastasis of gastric cancer and suggest that eIF4A1 is a potential target for the adjuvant therapy for gastric cancer patients.

scholarly journals Androgen receptor regulates eIF5A2 expression and promotes prostate cancer metastasis via EMT

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuancai Zheng ◽  
Ping Li ◽  
Hang Huang ◽  
Xueting Ye ◽  
Wei Chen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Elongation Factor ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Mesenchymal Transition ◽  
Invasion And Migration

AbstractAndrogen receptor (AR) is an androgen-activated transcription factor of the nuclear receptor superfamily. AR plays a role in the development and progression of prostate cancer (PCa). However, the exact role of AR in PCa metastasis remains unclear. In the present study, we aimed to elucidate the function of AR in PCa. We found that eukaryotic translation initiation factor (EIF) 5A2, an elongation factor that induces epithelial-to-mesenchymal transition (EMT) in PCa cells, was significantly upregulated after 5α-dihydrotestosterone (DHT) stimulation and downregulated after anti‐androgen bicalutamide treatment in PCa cells with high AR expression, but not in cells with low AR expression. Moreover, eIF5A2 knockdown could eliminate DHT-induced invasion and migration of AR-positive PCa cells. DHT treatment decreased epithelial expression of E‐cadherin and β-catenin but increased the expression of the mesenchymal marker proteins Vimentin and N-cadherin. DHT therefore induced EMT, and knockdown of eIF5A2 inhibited DHT-induced EMT. Moreover, in vivo study, Luciferase signals from the lungs of the eIF5A2 plasmid group indicated higher metastasis ability, and the eIF5A2 siRNA group had lower metastasis ability. Our results suggest that AR positively regulates eIF5A2 expression in androgen-dependent cells, and stimulation of AR expression and signaling in prostate tumors promotes PCa metastasis by EMT induction and upregulation of eIF5A2.

scholarly journals Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
YoungJun Ju ◽  
Yaacov Ben-David ◽  
Daniela Rotin ◽  
Eldad Zacksenhaus
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Translation Initiation ◽  
Triple Negative ◽  
Elongation Factor ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Related Factors ◽  
Metabolic Conditions

AbstractThe eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the ‘Collagen containing extracellular matrix’ pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.

Update on Phytochemical and Biological Studies on Rocaglate Derivatives from Aglaia Species

Planta Medica ◽  
2021 ◽  
Author(s):  
Garima Agarwal ◽  
Long-Sheng Chang ◽  
Djaja Doel Soejarto ◽  
A. Douglas Kinghorn
Keyword(s):  
Biological Activities ◽  
Chemical Constituents ◽  
Protein Translation ◽  
Biological Properties ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Ability To Act ◽  
Biological Studies ◽  
Phytochemical Constituents

AbstractWith about 120 species, Aglaia is one of the largest genera of the plant family Meliaceae (the mahogany plants). It is native to the tropical rainforests of the Indo-Australian region, ranging from India and Sri Lanka eastward to Polynesia and Micronesia. Various Aglaia species have been investigated since the 1960s for their phytochemical constituents and biological properties, with the cyclopenta[b]benzofurans (rocaglates or flavaglines) being of particular interest. Phytochemists, medicinal chemists, and biologists have conducted extensive research in establishing these secondary metabolites as potential lead compounds with antineoplastic and antiviral effects, among others. The varied biological properties of rocaglates can be attributed to their unusual structures and their ability to act as inhibitors of the eukaryotic translation initiation factor 4A (eIF4A), affecting protein translation. The present review provides an update on the recently reported phytochemical constituents of Aglaia species, focusing on rocaglate derivatives. Furthermore, laboratory work performed on investigating the biological activities of these chemical constituents is also covered.

scholarly journals The H1047R PIK3CA oncogene induces a senescence-like state, pleiotropy and acute HSP90 dependency in HER2+ mammary epithelial cells

2019 ◽  
Vol 40 (10) ◽  
pp. 1179-1190 ◽  
Author(s):  
Anindita Chakrabarty ◽  
Sreeraj Surendran ◽  
Neil E Bhola ◽  
Vishnu S Mishra ◽  
Tasaduq Hussain Wani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Breast Tumors ◽  
Genetically Engineered ◽  
Mammary Epithelial ◽  
Hsp90 Inhibition ◽  
Mesenchymal Transition ◽  
Pik3ca Mutations

Abstract In pre-clinical models, co-existence of Human Epidermal Growth Factor Receptor-2 (HER2)-amplification and PI3K catalytic subunit (PIK3CA) mutations results in aggressive, anti-HER2 therapy-resistant breast tumors. This is not always reflected in clinical setting. We speculated that the complex interaction between the HER2 and PIK3CA oncogenes is responsible for such inconsistency. We performed series of biochemical, molecular and cellular assays on genetically engineered isogenic mammary epithelial cell lines and breast cancer cells expressing both oncogenes. In vitro observations were validated in xenografts models. We showed that H1047R, one of the most common PIK3CA mutations, is responsible for endowing a senescence-like state in mammary epithelial cells overexpressing HER2. Instead of imposing a permanent growth arrest characteristic of oncogene-induced senescence, the proteome secreted by the mutant cells promotes stem cell enrichment, angiogenesis, epithelial-to-mesenchymal transition, altered immune surveillance and acute vulnerability toward HSP90 inhibition. We inferred that the pleiotropism, as observed here, conferred by the mutated oncogene, depending on the host microenvironment, contributes to conflicting pre-clinical and clinical characteristics of HER2+, mutated PIK3CA-bearing tumor cells. We also came up with a plausible model for evolution of breast tumors from mammary epithelial cells harboring these two molecular lesions.

scholarly journals Activation of GCN2 by the ribosomal P-stalk

2019 ◽  
Vol 116 (11) ◽  
pp. 4946-4954 ◽  
Author(s):  
Alison J. Inglis ◽  
Glenn R. Masson ◽  
Sichen Shao ◽  
Olga Perisic ◽  
Stephen H. McLaughlin ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Principal Component ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Exchange Mass Spectrometry ◽  
Hydrogen Deuterium ◽  
Hdx Ms ◽  
Ribosomal P

Cells dynamically adjust their protein translation profile to maintain homeostasis in changing environments. During nutrient stress, the kinase general control nonderepressible 2 (GCN2) phosphorylates translation initiation factor eIF2α, initiating the integrated stress response (ISR). To examine the mechanism of GCN2 activation, we have reconstituted this process in vitro, using purified components. We find that recombinant human GCN2 is potently stimulated by ribosomes and, to a lesser extent, by tRNA. Hydrogen/deuterium exchange–mass spectrometry (HDX-MS) mapped GCN2–ribosome interactions to domain II of the uL10 subunit of the ribosomal P-stalk. Using recombinant, purified P-stalk, we showed that this domain of uL10 is the principal component of binding to GCN2; however, the conserved 14-residue C-terminal tails (CTTs) in the P1 and P2 P-stalk proteins are also essential for GCN2 activation. The HisRS-like and kinase domains of GCN2 show conformational changes upon binding recombinant P-stalk complex. Given that the ribosomal P-stalk stimulates the GTPase activity of elongation factors during translation, we propose that the P-stalk could link GCN2 activation to translational stress, leading to initiation of ISR.

scholarly journals Causal Association Between mTOR-Dependent eIF4E mRNA Cap-Dependent Translation and Type 2 Diabetes: A Mendelian Randomization Study (OR31-02-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Ghada Soliman ◽  
C Mary Schooling
Keyword(s):  
Type 2 Diabetes ◽  
Sensitivity Analysis ◽  
Confidence Interval ◽  
Mendelian Randomization ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
P Value ◽  
Weighted Median

Abstract Objectives Type 2 diabetes is a prevalent chronic disease and is often associated with obesity and other comorbidities. The mammalian Target of Rapamycin complex 1 (mTORC1) nutrient-signaling pathway is a central regulator of cell growth and metabolism and is dysregulated in chronic diseases including diabetes and obesity. The eukaryotic translation initiation factor 4E (eIF-4E), a key regulator of gene translation and protein function, is under the control of mTOR and eIF4E Binding Proteins (4E-BPs). eIF-4E binds to the m7G (7-methylguanosine) cap at the 5’-UTR of most eukaryotic mRNA and mediates the recruitment of mRNA on ribosomes to start the protein translation. Both 4E-BP and ribosomal protein S6K kinase (S6K) are downstream effectors regulated by mTORC1 but converge to regulate two independent pathways. We investigated whether the risk of type 2 diabetes varied with genetically predicted eIF-4E and S6K levels using Mendelian Randomization (MR). Methods We estimated the causal role of eIF-4E and S6K plasma proteins, mTOR downstream targets, on type 2 diabetes, based on 16 single nucleotide polymorphisms (SNPs) for eIF-4E and 16 SNPs for S6K at P-value < 5x10−6. We applied these SNPs per exposure to publically available genetic associations with diabetes from the DIAbestes Genetics Replication And Meta-analysis (DIAGRAM) case (n = 26,676), and control (n = 132,532) study (mean age 57.4 years). We meta-analyzed SNP-specific Wald estimates using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median, and MR-Egger estimates. Results eIF-4E cap-dependent translation factor was associated with lowered risk of type 2 diabetes with an odds ratio (OR) 0.94 per effect size, 95% confidence interval (0.88, 0.99, P = 0.03) with similar estimates from the weighted median and MR-Egger. S6K was not associated with diabetes, OR 0.95, 95% confidence interval (0.89, 1.01, P = 0.08). Sensitivity analysis using MR-Egger and weighed median analysis did not indicate pleiotropic effects suggesting a unique protective effect of eIF-4E on type 2 diabetes. Conclusions This unbiased Mendelian Randomization estimate is consistent with a causally protective association of eIF-4E on type 2 diabetes. eIF-4E may be a target for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes. Funding Sources No specific funding.

scholarly journals The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

2020 ◽  
Vol 48 (7) ◽  
pp. 3816-3831 ◽  
Author(s):  
Tao Liu ◽  
Qinglv Wei ◽  
Jing Jin ◽  
Qingya Luo ◽  
Yi Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rna Modification ◽  
Dependent Manner ◽  
The Novel ◽  
A Subunit

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

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