Targeting immunogenic cell stress and death for cancer therapy

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(6), С. 445 - 460

Опубликована: Апрель 15, 2024

Язык: Английский

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Comprehensive review of Bcl‐2 family proteins in cancer apoptosis: Therapeutic strategies and promising updates of natural bioactive compounds and small molecules

Phytotherapy Research, Год журнала: 2024, Номер 38(5), С. 2249 - 2275

Опубликована: Фев. 28, 2024

Abstract Cancer has a considerably higher fatality rate than other diseases globally and is one of the most lethal profoundly disruptive ailments. The increasing incidence cancer among humans greatest challenges in field healthcare. A significant factor initiation progression tumorigenesis dysregulation physiological processes governing cell death, which results survival cancerous cells. B‐cell lymphoma 2 (Bcl‐2) family members play important roles several cancer‐related processes. Drug research development have identified various promising natural compounds that demonstrate potent anticancer effects by specifically targeting Bcl‐2 proteins their associated signaling pathways. This comprehensive review highlights substantial regulating apoptosis, including intricate pathways activity these proteins, impact reactive oxygen species, crucial involvement proteasome degradation stress response. Furthermore, this discusses advances exploration potential therapeutic applications small molecules thus provides scientific information strategies for management.

Язык: Английский

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DIO-SPOTlight Transgenic Mouse to Functionally Monitor Protein Synthesis Regulated by the Integrated Stress Response

Опубликована: Янв. 23, 2025

The integrated stress response (ISR) is a core pathway for maintaining cellular proteostasis and key regulator of translation in processes beyond the to stress. For example, ISR regulates developmental axonogenesis, learning memory, synaptic plasticity brain. One barrier uncovering roles health disease challenge monitoring its activity. transient nature regulatory phosphorylation events lack transgenic reporter mouse lines make visually capturing molecular hallmarks activation specific cell types especially difficult. We recently developed SPOTlight ( S elective P hospho-eIF2α O pen reading frame T racking light) reporter, which uniquely provides readout functional state protein synthesis initiation dynamics that are regulated by ISR. Here, we report generation line with Cre-dependent expression SPOTlight. This resource enables selective visualization ISR-regulated activity across genetically defined populations body-wide. Using pan-neuronal Cre Nestin -Cre), demonstrate reporter’s performance applications cell-specific discovery, live tissue assessments quantitative comparisons broad physical space. also specifically investigated extent property steady-state basal activation, described dorsal striatal cholinergic interneurons, extends other classes neurons provide CNS-wide atlas these cells. DIO-SPOTlight wide range studies all organ systems opportunities not previously accessible.

Язык: Английский

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Mitochondria driven innate immune signaling and inflammation in cancer growth, immune evasion, and therapeutic resistance

International review of cell and molecular biology, Год журнала: 2024, Номер unknown, С. 223 - 247

Опубликована: Янв. 1, 2024

Язык: Английский

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DIO-SPOTlight Transgenic Mouse to Functionally Monitor Protein Synthesis Regulated by the Integrated Stress Response

Опубликована: Янв. 23, 2025

The integrated stress response (ISR) is a core pathway for maintaining cellular proteostasis and key regulator of translation in processes beyond the to stress. For example, ISR regulates developmental axonogenesis, learning memory, synaptic plasticity brain. One barrier uncovering roles health disease challenge monitoring its activity. transient nature regulatory phosphorylation events lack transgenic reporter mouse lines make visually capturing molecular hallmarks activation specific cell types especially difficult. We recently developed SPOTlight ( S elective P hospho-eIF2α O pen reading frame T racking light) reporter, which uniquely provides readout functional state protein synthesis initiation dynamics that are regulated by ISR. Here, we report generation line with Cre-dependent expression SPOTlight. This resource enables selective visualization ISR-regulated activity across genetically defined populations body-wide. Using pan-neuronal Cre Nestin -Cre), demonstrate reporter’s performance applications cell-specific discovery, live tissue assessments quantitative comparisons broad physical space. also specifically investigated extent property steady-state basal activation, described dorsal striatal cholinergic interneurons, extends other classes neurons provide CNS-wide atlas these cells. DIO-SPOTlight wide range studies all organ systems opportunities not previously accessible.

Язык: Английский

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CRISPuRe-seq: pooled screening of barcoded ribonucleoprotein reporters reveals regulation of RNA polymerase III transcription by the integrated stress response via mTOR

Nucleic Acids Research, Год журнала: 2025, Номер 53(4)

Опубликована: Янв. 23, 2025

Genetic screens using CRISPR (Clustered Regularly Interspaced Palindromic Repeats) provide valuable information about gene function. Nearly all pooled screening technologies rely on the cell to link genotype phenotype, making it challenging assay mechanistically informative, biochemically defined phenotypes. Here, we present CRISPuRe-seq (CRISPR PuRification), a novel strategy that expands universe of accessible phenotypes through purification ribonucleoprotein complexes genotypes expressed RNA barcodes. While for regulators integrated stress response (ISR), serendipitously discovered ISR represses transfer (tRNA) production under conditions reduced protein synthesis. This regulation is mediated inhibition mTORC1 and corresponding activation polymerase III inhibitor MAF1. These data demonstrate coherent downregulation tRNA expression synthesis achieved cross-talk between mTOR, two master integrators state.

Язык: Английский

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Routine Blood Tests as Predictive Tools for Differentiating Follicular Thyroid Carcinoma From Follicular Adenoma

International Journal of General Medicine, Год журнала: 2025, Номер Volume 18, С. 733 - 744

Опубликована: Фев. 1, 2025

Background: Thyroid cancer is the most common endocrine malignancy, with an increasing incidence rate, particularly among adolescents. Follicular thyroid carcinoma (FTC), though less than papillary (PTC), presents greater diagnostic challenges, especially when differentiating from follicular adenoma (FA). Current methods lack specificity, underscoring need for a simple, cost-effective predictive model FTC.This study aimed to develop scoring system based on routine blood biomarkers distinguish between FTC and FA, facilitating early diagnosis treatment. Methods: A retrospective, single-center case-control was conducted patients diagnosed FA at Renmin Hospital of Wuhan University 2016 2022. Patients' demographic, clinicopathological characteristics, preoperative biomarker data were analyzed. Statistical tests, including chi-square, t-tests, Mann–Whitney U -tests, used compare biomarkers. Significant variables included in univariate multivariate logistic regression analyses, leading development system. The model's performance assessed using receiver operating characteristic (ROC) curves. Results: 23 26 FTC. Seven showed significant differences groups: ALB, DBIL, TBIL, LYM#, MCHC, RDW-SD, WBC. Multivariate identified ALB WBC as key predictors, forming (Score = 0.54 × - 1.10 WBC). exhibited strong (AUC 0.839), sensitivity specificity 0.808 0.826, respectively. Conclusion: developed novel biomarkers, offering non-invasive, tool FA. has clinical potential, providing feasible alternative conventional techniques. Further multicenter studies mechanistic investigations are warranted validate refine model, enhancing its utility practice. Keywords: carcinoma, albumin,

Язык: Английский

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Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 13, 2025

The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. integrated stress response (ISR) is a key adaptive pathway that enables survival under oncogenic stress. While ISR has been implicated promoting growth, precise driving evolution not elucidated. In this study, using genetically engineered mouse models, we demonstrate activation-indicated by elevated levels phosphorylated eIF2 (p-eIF2) ATF4-is essential for emergence dedifferentiated, therapy-resistant cell states. ISR, through coordinated actions ATF4 MYC, facilitates development populations characterized high plasticity, stemness, an epithelial-mesenchymal transition (EMT)-prone phenotype. This process driven ISR-mediated expression genes maintain mitochondrial integrity function, critical sustaining progression. Importantly, genetic, or pharmacological inhibition p-eIF2-ATF4 signaling axis leads to dysfunction significantly impairs growth models lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation associated with poor prognosis therapy resistance advanced human LUAD, underscoring as promising therapeutic strategy disrupt counteract disease

Язык: Английский

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Inhibition of the Integrated stress response by Epstein-Barr virus oncoprotein LMP1 attenuates epithelial cell differentiation and lytic viral reactivation

PLoS Pathogens, Год журнала: 2025, Номер 21(2), С. e1012934 - e1012934

Опубликована: Фев. 14, 2025

EBV infects normal oral keratinocytes (NOKs) and plays an essential role in undifferentiated nasopharyngeal carcinoma (NPC). We previously showed that the oncogene, LMP1, promotes proliferation inhibits spontaneous differentiation telomerase-immortalized NOKs grown growth factor-restricted conditions. Here we have further examined phenotypes of infected with wild-type (WT EBV) versus LMP1-deleted mutant (ΔLMP1 RNA-seq results show WT EBV-infected not only reduced differentiation, but also decreased expression genes activated by integrated stress response (ISR) pathway, comparison to ΔLMP1 cells. The ISR pathway is mediated increased phosphorylation eIF2α translation initiation factor, leading most cellular proteins some proteins, including ATF4 CHOP. Immunoblot analyses confirmed uninfected cells LMP1 alone sufficient inhibit phosphorylation. found decreases activity two different kinases, PERK GCN2, NOKs, resulting ISR-induced transcription factors, CHOP, NOKs. Furthermore, both GCN2 are required for efficient TPA-induced lytic reactivation TPA-mediated epithelial cell differentiation. In addition, demonstrate over-expression CHOP induce NPC this effect activation differentiation-inducing KLF4 BLIMP1. Our suggest inhibition oncoprotein, may promote early development preventing reactivation.

Язык: Английский

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Unravelling the antitumor mechanism of Ocoxin through cancer cell genomics

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 19, 2025

Cancer is one of the leading causes death worldwide. Many therapies are being used to treat this disease, however, new treatments now implemented, since they not always effective and their secondary effects represent main reasons for cancer patients’ loss life quality during progression disease. In scenario, Ocoxin a mixture plant extracts, amino acids, vitamins minerals, known its antioxidant, anti-inflammatory immunoregulatory properties, which has shown exert antitumor in many cancers. The aim study elucidate mechanism action compound colorectal cancer, triple negative breast pancreatic prostate cancer. Analyses performed through RNA sequencing revealed that effect appears be alteration cell metabolism, especially inducing process ferroptosis. Nevertheless, modulation cycle was also remarkable. altered 13 genes common all four cancers were only associated metabolism but involved integrated stress response unfolded protein response, suggesting induction several pathways. Although mechanisms vary according type highlights potential as an adjunctive treatment improve outcomes therapy.

Язык: Английский

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