Inhibition of GCN2 Reveals Synergy with Cell-Cycle Regulation and Proteostasis DOI Creative Commons
Gregory Gauthier-Coles, Farid Rahimi,

Angelika Bröer

и другие.

Metabolites, Год журнала: 2023, Номер 13(10), С. 1064 - 1064

Опубликована: Окт. 9, 2023

The integrated stress response is a signaling network comprising four branches, each sensing different cellular stressors, converging on the phosphorylation of eIF2α to downregulate global translation and initiate recovery. One these branches includes GCN2, which senses amino acid insufficiency participates in maintaining homeostasis. Previous studies have shown that GCN2 viable cancer target when induced by inhibiting an additional target. In this light, we screened numerous drugs for their potential synergize with inhibitor TAP20. drug sensitivity six cell lines panel 25 compounds was assessed. Each compound then combined TAP20 at concentrations below IC50, impact growth evaluated. strongly synergistic combinations were further characterized using synergy analyses matrix-dependent invasion assays. Inhibitors proteostasis MEK-ERK pathway, as well pan-CDK inhibitors, flavopiridol, seliciclib, potently two lines. Among common CDK targets CDK7, more selectively targeted THZ-1 synergized Moreover, partially assessed However, alone sufficient restrict its growth-inhibitory IC50. We conclude inhibition can be explored vivo

Язык: Английский

Beyond genetics: driving cancer with the tumour microenvironment behind the wheel DOI
Shaopeng Yuan, Jorge Almagro, Elaine Fuchs

и другие.

Nature reviews. Cancer, Год журнала: 2024, Номер 24(4), С. 274 - 286

Опубликована: Фев. 12, 2024

Язык: Английский

Процитировано

50
Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response DOI
Ronald C. Wek, Tracy G. Anthony, Kirk A. Staschke

и другие.

Antioxidants and Redox Signaling, Год журнала: 2023, Номер 39(4-6), С. 351 - 373

Опубликована: Март 21, 2023

Organisms adapt to changing environments by engaging cellular stress response pathways that serve restore proteostasis and enhance survival. A primary adaptive mechanism is the integrated (ISR), which features phosphorylation of α subunit eukaryotic translation initiation factor 2 (eIF2). Four eIF2α kinases respond different stresses, enabling cells rapidly control optimize management resources reprogram gene expression for adaptation. Phosphorylation eIF2 blocks its guanine nucleotide exchange factor, eIF2B, thus lowering levels bound GTP required deliver initiator transfer RNA (tRNA) ribosomes. While bulk messenger (mRNA) can be sharply lowered heightened eIF2α, there are other transcripts whose unchanged or preferentially translated. Among translated genes

Язык: Английский

Процитировано

33
Activation of Gcn2 by small molecules designed to be inhibitors DOI Creative Commons
Kenneth Carlson,

Millie M Georgiadis,

Feven Tameire

и другие.

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(4), С. 104595 - 104595

Опубликована: Март 8, 2023

Язык: Английский

Процитировано

31
The integrated stress response in cancer progression: a force for plasticity and resistance DOI Creative Commons
Caleb L. Lines, Morgan J. McGrath, Tanis J. Dorwart

и другие.

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Авг. 3, 2023

During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation deplete tumor microenvironment resources. As dynamic adaptation self-imposed oncogenic stress, promptly hijack translational control alter gene expression. Rewiring proteome shifts phenotypic balance between growth promote therapeutic resistance cell survival. The integrated stress response (ISR) is key program activated by that utilized fine-tune synthesis adjust environmental barriers. Here, we focus on role ISR signaling driving progression. We highlight mechanisms regulation distinct mRNA translation downstream ISR, expand utilizing in stresses, pinpoint impact this has plasticity during therapy. There an ongoing need innovative drug targets treatment, modulating activity may provide unique avenue clinical benefit.

Язык: Английский

Процитировано

26
GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis DOI Creative Commons
Ricardo A. Cordova, Jagannath Misra,

Parth H. Amin

и другие.

eLife, Год журнала: 2022, Номер 11

Опубликована: Сен. 15, 2022

A stress adaptation pathway termed the integrated response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that eIF2 kinase GCN2 is required for sustained growth androgen-sensitive and castration-resistant models of PCa both vitro vivo, patient samples. Using RNA-seq transcriptome analysis a CRISPR-based phenotypic screen, was shown regulate expression over 60 solute-carrier ( SLC ) genes, those involved amino acid transport loss function reduces import levels. Addition essential acids or 4F2 (SLC3A2) partially restored following GCN2, suggesting targeting transporters homeostasis needed sustain tumor growth. small molecule inhibitor showed robust vivo efficacy mouse PCa, supporting its therapeutic potential treatment PCa.

Язык: Английский

Процитировано

38
Multiple Roles of the Stress Sensor GCN2 in Immune Cells DOI Open Access

Chenxu Zhao,

Han Guo, Yangxiao Hou

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(5), С. 4285 - 4285

Опубликована: Фев. 21, 2023

The serine/threonine-protein kinase general control nonderepressible 2 (GCN2) is a well-known stress sensor that responds to amino acid starvation and other stresses, making it critical the maintenance of cellular organismal homeostasis. More than 20 years research has revealed molecular structure/complex, inducers/regulators, intracellular signaling pathways bio-functions GCN2 in various biological processes, across an organism’s lifespan, many diseases. Accumulated studies have demonstrated also closely involved immune system immune-related diseases, such as acts important regulatory molecule macrophage functional polarization CD4+ T cell subset differentiation. Herein, we comprehensively summarize functions discuss its roles system, including innate adaptive cells. We antagonism mTOR A better understanding GCN2′s under physiological, stressful, pathological situations will be beneficial development potential therapies for immune-relevant

Язык: Английский

Процитировано

18
Cellular Stress: Modulator of Regulated Cell Death DOI Creative Commons
Prem Prasad Lamichhane, Parimal Samir

Biology, Год журнала: 2023, Номер 12(9), С. 1172 - 1172

Опубликована: Авг. 25, 2023

Cellular stress response activates a complex program of an adaptive called integrated (ISR) that can allow cell to survive in the presence stressors. ISR reprograms gene expression increase transcription and translation genes while repressing most proteins reduce metabolic burden. In some cases, activation lead assembly cytoplasmic membraneless compartment granules (SGs). SGs inhibit apoptosis, pyroptosis, necroptosis, suggesting they guard against uncontrolled regulated death (RCD) promote organismal homeostasis. However, also cancer cells stressful environments, including hypoxia during chemotherapy. Therefore, there is great need understand molecular mechanism crosstalk between RCD. This active area research expected be relevant range human diseases. this review, we provided overview interplay different cellular responses RCD pathways their modulation health disease.

Язык: Английский

Процитировано

14
The human LAT1–4F2hc (SLC7A5–SLC3A2) transporter complex: Physiological and pathophysiological implications DOI Creative Commons
Jennifer Kahlhofer, David Teis

Basic & Clinical Pharmacology & Toxicology, Год журнала: 2022, Номер 133(5), С. 459 - 472

Опубликована: Дек. 3, 2022

Abstract LAT1 and 4F2hc form a heterodimeric membrane protein complex, which functions as one of the best characterized amino acid transporters. Since LAT1–4F2hc is required for efficient uptake essential acids hormones, it promotes cellular growth, in part, by stimulating mTORC1 (mechanistic target rapamycin complex 1) signalling repressing integrated stress response (ISR). Gain or loss function associated with cancer, diabetes, immunological neurological diseases. Hence, represents an attractive drug disease treatment. Specific targeting will be facilitated increasingly detailed understanding its molecular architecture, provides important concepts regulation. Here, we summarize (i) structural insights that help to explain how assemble transport across membranes, (ii) role key metabolic pathways, (iii) derailing these processes could contribute

Язык: Английский

Процитировано

19
TFE3-splicing factor fusions represent functional drivers and druggable targets in translocation renal cell carcinoma DOI
Nur P. Damayanti, Ricardo A. Cordova, Christopher Rupert

и другие.

Cancer Research, Год журнала: 2024, Номер 84(8), С. 1286 - 1302

Опубликована: Янв. 24, 2024

Abstract TFE3 is a member of the basic helix–loop–helix leucine zipper MiT transcription factor family, and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite variety gene fusions, most fusion partner genes related to spliceosome machinery. Dissecting function fused machinery factors (TFE3-SF) could direct development effective therapies for this lethal disease, which refractory standard treatments kidney cancer. Here, by using combination in silico structure prediction, transcriptome profiling, molecular characterization, high-throughput high-content screening (HTHCS), we interrogated number oncogenic mechanisms TFE3-SF fusions. fusions drove transformation cells promoted distinct phenotypes partner-dependent manner, differentially altering RNA splicing landscape activating different pathways. Inhibiting dimerization reversed activity represented potential target therapeutic intervention. Screening FDA-approved drugs library LOPAC small-molecule (Microsource) HTHCS combined FRET technology identified compounds that inhibit dimerization. Hit were validated 2D 3D patient-derived xenograft models expressing TFE3-SF. The antihistamine terfenadine decreased proliferation reduced vivo tumor growth tRCC. Overall, these results unmask strategies treating patients Significance: TFE3-splicing possess both functions remodel can be targeted inhibitors suppress carcinoma.

Язык: Английский

Процитировано

3
Hypusinated and unhypusinated isoforms of the translation factor eIF5A exert distinct effects in models of pancreas development and function DOI Creative Commons
Thomas Anderson, Abhishek Kulkarni, Bernhard Maier

и другие.

Journal of Biological Chemistry, Год журнала: 2025, Номер 301(2), С. 108209 - 108209

Опубликована: Янв. 18, 2025

Hypusination of eukaryotic translation initiation factor 5A (eIF5A) is essential for its role in elongation and termination. Although the function hypusinated eIF5A (eIF5AHyp) cellular proliferation well characterized, unhypusinated form (eIF5ALys) remains unclear. We hypothesized that eIF5ALys exerts independent negative effects on replication metabolism, distinct from loss eIF5AHyp. To test this hypothesis, we utilized zebrafish mouse models with inducible knockdowns deoxyhypusine synthase (DHPS) to investigate their roles growth. Gene expression analysis via RNA sequencing morphometric measurements pancreas β-cell mass were performed assess phenotypic changes identify affected biological pathways. Loss DHPS resulted significant defects pancreatic growth, accompanied by gene related mRNA translation, neurogenesis, stress By contrast, knockdown had minimal impact development, suggesting are not solely because lack In mice, β-cell-specific deletion impaired expansion glucose tolerance, whereas no statistically effects. These findings provide evidence an regulating developmental functional responses health disease.

Язык: Английский

Процитировано

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