Role of p53 in breast cancer progression: An insight into p53 targeted therapy

Theranostics, Journal Year: 2023, Volume and Issue: 13(4), P. 1421 - 1442

Published: Jan. 1, 2023

The transcription factor p53 is an important regulator of a multitude cellular processes.In the presence genotoxic stress, activated to facilitate DNA repair, cell cycle arrest, and apoptosis.In breast cancer, tumor suppressive activities are frequently inactivated by either overexpression its negative MDM2, or mutation which present in 30-35% all cancer cases.Notably, frequency highly subtype dependent cancers, with majority hormone receptor-positive luminal subtypes retaining wild-type status while receptor-negative patients predominantly carry mutations gain-of-function oncogenic that contribute poorer prognosis.Thus, two-pronged strategy targeting mutant different can have clinical relevance.The development p53-based therapies has rapidly progressed recent years, include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well several genetic-based approaches using vectors engineered antibodies.In this review, we highlight therapeutic strategies pre-clinical overcome inactivation both p53-bearing tumors, discuss their efficacies limitations settings.

Language: Английский

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The role of NF-κB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 163, P. 114822 - 114822

Published: May 3, 2023

Breast cancer (BC) is the second most fatal disease and prime cause of allied female deaths. BC caused by aberrant tumor suppressor genes oncogenes regulated transcription factors (TFs) like NF-κB. NF-κB a pro-inflammatory TF that crucially alters expressions various associated with inflammation, cell progression, metastasis, apoptosis modulates network underlie tumorigenesis. Herein, we focus on signaling pathways, its regulators, rationale for targeting This review also includes TFs maintain crosstalk their roles in promoting angiogenesis metastasis. In addition, discuss importance combination therapies, resistance to treatment, potential novel therapeutic strategies including nanomedicine targets

Language: Английский

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The mechanism of ferroptosis and its related diseases

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Oct. 16, 2023

Abstract Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation lipid peroxides, provides novel avenue for delving into intersection metabolism, oxidative stress, and disease pathology. We have witnessed mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, traumatic tissue injuries. By unraveling intricate underpinnings molecular machinery, contributors, signaling conduits, regulatory networks governing researchers aim bridge gap between intricacies this unique mode multifaceted implications health disease. In light rapidly advancing landscape ferroptosis research, we present comprehensive review aiming at extensive in origins progress human diseases. This concludes careful analysis potential treatment approaches carefully designed either inhibit or promote ferroptosis. Additionally, succinctly summarized therapeutic targets compounds that hold promise targeting within various facet underscores burgeoning possibilities manipulating as strategy. summary, enriched insights both investigators practitioners, while fostering an elevated comprehension latent translational utilities. revealing basic processes investigating possibilities, crucial resource scientists medical aiding deep understanding effects situations.

Language: Английский

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Cancer chemotherapy resistance: Mechanisms and recent breakthrough in targeted drug delivery

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 958, P. 176013 - 176013

Published: Aug. 24, 2023

Language: Английский

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Heavy metals: toxicity and human health effects

Archives of Toxicology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 20, 2024

Abstract Heavy metals are naturally occurring components of the Earth’s crust and persistent environmental pollutants. Human exposure to heavy occurs via various pathways, including inhalation air/dust particles, ingesting contaminated water or soil, through food chain. Their bioaccumulation may lead diverse toxic effects affecting different body tissues organ systems. The toxicity depends on properties given metal, dose, route, duration (acute chronic), extent bioaccumulation. detrimental impacts human health largely linked their capacity interfere with antioxidant defense mechanisms, primarily interaction intracellular glutathione (GSH) sulfhydryl groups (R-SH) enzymes such as superoxide dismutase (SOD), catalase, peroxidase (GPx), reductase (GR), other enzyme Although arsenic (As) is believed bind directly critical thiols, alternative hydrogen peroxide production processes have also been postulated. known signaling pathways affect a variety cellular processes, cell growth, proliferation, survival, metabolism, apoptosis. For example, cadmium can BLC-2 family proteins involved in mitochondrial death overexpression antiapoptotic Bcl-2 suppression proapoptotic (BAX, BAK) thus increasing resistance cells undergo malignant transformation. Nuclear factor erythroid 2-related 2 (Nrf2) an important regulator enzymes, level oxidative stress, oxidants has shown act double-edged sword response arsenic-induced stress. Another mechanism significant threats metal (e.g., Pb) involves substitution essential calcium (Ca), copper (Cu), iron (Fe)) structurally similar (Cd) (Pb)) metal-binding sites proteins. Displaced redox (copper, iron, manganese) from natural catalyze decomposition Fenton reaction generate damaging ROS hydroxyl radicals, causing damage lipids, proteins, DNA. Conversely, some metals, cadmium, suppress synthesis nitric oxide radical (NO · ), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced stress be indirectly responsible for depletion due its (O ·− resulting formation potent biological oxidant, peroxynitrite (ONOO − ). This review comprehensively discusses mechanisms effects. Aluminum (Al), (Cd), (As), mercury (Hg), (Pb), chromium (Cr) roles development gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer’s Parkinson’s diseases), cardiovascular, cancer (e.g. renal, lung, skin, stomach) diseases discussed. A short account devoted detoxification chelation use ethylenediaminetetraacetic acid ( EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic (DMSA), 2,3-dimercapto-1-propane sulfonic (DMPS), penicillamine chelators.

Language: Английский

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Deciphering the suppressive immune microenvironment of prostate cancer based on CD4+ regulatory T cells: Implications for prognosis and therapy prediction

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(1)

Published: Jan. 1, 2024

Dear Editor, Prostate cancer (PCa) is traditionally considered an immunologically cold tumour characterized by immunosuppressive microenvironment (TME) and a disappointing response to immunotherapy. Nevertheless, recent studies have demonstrated that the TME of PCa heterogeneous, some patients still exhibit “hot tumours” are sensitive immunotherapy.1 Our prior works also classified into three phenotypes according variable immune status emphasized important role regulatory T (Treg) cells in shaping exhausted PCa.2 In this study, we further conducted in-depth discussion on Treg cells, detailed methods listed Supporting Information Data. A total 56924 from 14 samples with Gleason scores were clustered annotated 13 cell types, where high attracted much attention (Figure 1A–C Figure S1). We extracted re-clustered all 11 clusters S2A). Referring published articles, these six populations 1D–F S2B), C3 exhibited highest score (p < 2.2e-16) C5 had Th17 2.1e-16); as 1G). The ratio positively correlated groups = .04, R 0.65; 1H S2C), which was comfited external dataset (HRA000823, p .039, 0.56; S3), indicating positive correlation between infiltration poor prognosis. multiplex immunofluorescence experiment, more CD4+FOXP+Treg observed high-risk (Gleason 4+5, PSA > 100 ng/dL, T3bN1M0) than low-risk 3+4, 25.39 T2N0M0) 1I). addition, abundances CD8+effector, CTL, activate B plasma increased groups, SPP1+macrophage presented while no significance showed (Figures S4–S6). Trajectory analysis revealed differentiated distinct directions 2A), expression patterns branch-dependent genes different. As shown 2B, G3 toward branch 2 enriched negative regulation system processes, might better represent mature cells. Based cluster S7 S8), assigned TCGA-PRAD cohort two 2C): P2 poorer prognosis .001, hazards [HR] 4.34, 95% confidence interval [CI]: 2.564–7.344), higher activity 3.39e-11), thereby nomenclature rich-Treg (TregR) P1 poor-Treg (TregP) 2D,E). Notably, inflammation S9). Compared TregP, TregR for immune-suppressed signatures, such transforming growth factor-β (TGF-β), myeloid-derived suppressor (MDSC), tertiary lymphoid structure (TLS) programmed death 1 (PD-1) signatures 2F). Interestingly, subtype, TGF-β be pivotal enforcer tolerance homeostasis. Peripheral CD4+ reportedly produce under suboptimal stimulation, initiating transformation malignant cells.3 secrete abundant TGF-β, inhibiting CD8+ thus advancing progression.4 Jiao et al. essential suppressive PCa. common result, immunotherapy combined inhibition may treatment option improve survival rates.5 cohorts, risk recurrence 6-fold greater TregP real-world AHMU-PC .001) 2-fold MSKCC .026) GSE23136 cohorts 3). Similar trends, elevated MDSC, TLS PD-1 consistent across S10). Multiple somatic nucleotide variations underlie heterogeneity PCa, mutation landscapes S11 Table S4), among mutational differences TP53 PIK3CA our 4A). Variants gene predisposed aggressive chemoresistance sensitivity anti-PD-1 therapy,6-8 one explanations limited available treatments TregR. Among enrolled eight chemicals, only cisplatin .004) 5-fluorouracil .028) effective against TregR, bicalutamide 4.2e-11), doxorubicin 5.3e-06), etoposide 1.9e-10), gemcitabine .00053), mitomycin C .0021) vinorelbine 2e-08) 4B), well therapy 4C). Overall, susceptibility subtypes drugs broadly except S12). upstream effector PI3K-AKT-mTOR pathway, PI3K activation usually occurs advanced tumours PI3KA mutations nearly 28%–30% castration-resistant PCa.9 pathway aberrantly activated when AR receptors strongly inhibited, contributes bicalutamide.10 On other hand, inhibitors BKM120 PX966 help restore compared PCa-Treg classification proposed classifications 4D); information Supplementary Methods. belonged PMOC2, weak androgen deprivation (ADT) frequency TP53, resulting prognosis, 4E). overlap TregR/PMOC2 defined worst phenotype .0001, S13A). TregRs luminal subtype 4E), TregR/luminal group poorest .0001; S13B). clinical features PMOC2 indicated stability molecular typing extent. Although determined many factors, Tregs heavily weighted. single-cell bulk RNA sequencing verify driving Two defined, represented immunosuppressed therapeutic opposite. Characteristics facilitate resistance or ADT, needed explore specific underlying mechanisms, will us overcome ADT reverse “cold” Conceptualization, QG, ZZ XL; methodology, ZZ, XL JM; formal analysis, FY investigation, MZ, JM, CL; writing original draft, JM ZZ; visualization, QG funding acquisition, ZH supervision, ZH, CL. greatly appreciate investigators who participated corresponding medical project providing data. appreciated technique support Dr. Zhao Zhijie. authors declare conflict interest. This work supported Anhui Province Key Project Clinical Medical Research Translation Advancement (202204295107020031). Ethical approval study obtained Ethics Committee First Affiliated Hospital University (approval number: PJ-2019-09-11). Please note: publisher not responsible content functionality any supporting supplied authors. Any queries (other missing content) should directed author article.

Language: Английский

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Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(3), P. 297 - 360

Published: Feb. 4, 2024

Abstract Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well immunotherapy have benefited cancer patients considerably. Tumor protein p53 ( TP53 ), crucial tumor suppressor gene encoding p53, regulates numerous downstream genes cellular phenotypes response to various stressors. The affected are involved diverse processes, including cell cycle arrest, DNA repair, senescence, metabolic homeostasis, apoptosis, autophagy. However, accumulating recent studies continued reveal novel unexpected functions governing the fate tumors, for example, ferroptosis, immunity, microenvironment microbiome metabolism. Among possibilities, evolutionary plasticity most controversial, partially due dizzying array biological that been attributed different regulatory mechanisms signaling. Nearly 40 years after its discovery, this remains somewhat enigmatic. intricate regulating during treatment only tip iceberg respect equally complicated structural biology, which has painstakingly revealed. Additionally, mutation one significant genetic alterations cancer, contributing rapid growth progression. Here, we summarized advances implicate altered modulating therapies, chemotherapy, radiotherapy, immunotherapy. Furthermore, also discussed potential strategies targeting therapeutic option cancer.

Language: Английский

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ERK pathway agonism for cancer therapy: evidence, insights, and a target discovery framework

npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)

Published: March 14, 2024

At least 40% of human cancers are associated with aberrant ERK pathway activity (ERKp). Inhibitors targeting various effectors within the ERKp have been developed and explored for over two decades. Conversely, a substantial body evidence suggests that both normal cells and, notably to greater extent, cancer exhibit susceptibility hyperactivation ERKp. However, this vulnerability remains relatively unexplored. In review, we reexamine on selective lethality highly elevated in varying backgrounds. We synthesize insights proposed harnessing ERK-associated therapeutical approaches contextualize these established pharmacological cancer-targeting models. Moreover, compile intriguing preclinical findings agonism diverse Lastly, present conceptual framework target discovery regarding agonism, emphasizing utilization mutual exclusivity among oncogenes develop novel targeted therapies precision oncology.

Language: Английский

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The impact of ribosome biogenesis in cancer: from proliferation to metastasis

NAR Cancer, Journal Year: 2024, Volume and Issue: 6(2)

Published: April 8, 2024

Abstract The dysregulation of ribosome biogenesis is a hallmark cancer, facilitating the adaptation to altered translational demands essential for various aspects tumor progression. This review explores intricate interplay between and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal multifaceted roles ribosomes, extending beyond protein factories include regulatory functions in mRNA translation. Dysregulated not only hampers precise control global production proliferation but also influences processes such as maintenance stem cell-like properties epithelial-mesenchymal transition, contributing Interference with biogenesis, notably through RNA Pol I inhibition, elicits stress response marked nucleolar integrity loss, subsequent G1-cell cycle arrest or cell death. These findings suggest that cells may rely on heightened transcription, rendering ribosomal synthesis potential therapeutic vulnerability. further targeting vulnerabilities promising strategy disrupt production, presenting opportunities treatment.

Language: Английский

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Nanoscale Metal–Organic Frameworks‐Mediated Degradation of Mutant p53 Proteins and Activation of cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Advanced Science, Journal Year: 2024, Volume and Issue: 11(12)

Published: Jan. 15, 2024

Abstract Activating cGAS‐STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance pathway. Herein, multifunctional ZIF‐8@MnO 2 nanoparticles are constructed degrade mutp53 and facilitate The synthesized can release Zn 2+ Mn cancer cells induce oxidative stress cytoplasmic leakage fragmented mitochondrial double‐stranded DNAs (dsDNAs). Importantly, released induces variable degradation multifarious mutants through proteasome ubiquitination, which alleviate inhibitory effects on In addition, further increases sensitivity cGAS dsDNAs as immunostimulatory signals. Both vitro vivo results demonstrate that effectively promotes synergizes with PD‐L1 checkpoint blockades, leading remarkable regression local tumors well distant metastases breast cancer. This study proposes an inorganic metal ion‐based nanoplatform enhance cGAS‐STING‐mediated immunotherapy, especially those expression.

Language: Английский

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