Pharmacological CDK4/6 inhibition promotes vulnerability to lysosomotropic agents in breast cancer

The EMBO Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 10, 2025

Breast cancer is a leading cause of mortality worldwide. Pharmacological inhibitors cyclin-dependent kinases (CDK) 4 and 6 (CDK4/6i) inhibit breast growth by inducing senescent-like state. However, the long-term treatment efficacy remains limited development drug resistance, so clearance cells may extend durability treatment. we show here that while CDK4/6i-treated exhibit various senescence-associated phenotypes, they remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, identify significantly increased lysosomal mass altered structure across cell types upon exposure CDK4/6i in preclinical systems clinical specimens. We demonstrate these CDK4/6i-induced alterations render sensitive lysosomotropic agents, such as L-leucyl-L-leucine methyl ester (LLOMe) salinomycin. Importantly, sequential with agents effectively reduces both hormone receptor-positive (HR+) subsets triple-negative (TNBC) vivo. This therapeutic strategy offers promising approach eliminate senescent(-like) cells, potentially reducing tumor recurrence enhancing overall therapy.

Язык: Английский

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A Feedback Loop Driven by H4K12 Lactylation and HDAC3 in Macrophages Regulates Lactate‐Induced Collagen Synthesis in Fibroblasts Via the TGF‐β Signaling

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 13, 2025

Abstract The decrease in fibroblast collagen is a primary contributor to skin aging. Lactate can participate synthesis through lysine lactylation by regulating gene transcription. However, the precise mechanism which lactate influences requires further investigation. This study demonstrates that depletion of macrophages mitigates stimulating effect on fibroblasts. Through joint CUT&Tag and RNA‐sequencing analyses, feedback loop between H4K12 (H4K12la) histone deacetylase 3 (HDAC3) drives lactate‐induced are identified. Macrophages uptake extracellular via monocarboxylate transporter‐1 (MCT1), leading an up‐regulation H4K12la levels KAT5‐KAT8‐dependent response Poly‐L‐Lactic Acid (PLLA) stimulation, source low concentration persistent lactate, thereby promoting Furthermore, enriched at promoters TGF‐β1 TGF‐β3, enhancing their Hyperlactylation inhibits expression eraser HDAC3, while activation HDAC3 reduces suppresses In conclusion, this illustrates play critical role skin, targeting lactate‐H4K12la‐HDAC3‐TGF‐β axis may represent novel approach for production combat

Язык: Английский

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Targeting lysosomal quality control as a therapeutic strategy against aging and diseases

Medicinal Research Reviews, Год журнала: 2024, Номер 44(6), С. 2472 - 2509

Опубликована: Май 6, 2024

Previously, lysosomes were primarily referred to as the digestive organelles and recycling centers within cells. Recent discoveries have expanded lysosomal functional scope revealed their critical roles in nutrient sensing, epigenetic regulation, plasma membrane repair, lipid transport, ion homeostasis, cellular stress response. Lysosomal dysfunction is also found be associated with aging several diseases. Therefore, function of macroautophagy, a lysosome-dependent intracellular degradation system, has been identified one updated twelve hallmarks aging. In this review, we begin by introducing concept quality control (LQC), which machinery that maintains number, morphology, through different processes such biogenesis, reformation, fission, fusion, turnover, lysophagy, exocytosis, permeabilization repair. Next, summarize results from studies reporting association between LQC dysregulation aging/various disorders. Subsequently, explore emerging therapeutic strategies target distinct aspects for treating diseases combatting Lastly, underscore existing knowledge gap propose potential avenues future research.

Язык: Английский

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Unraveling the potential of neuroinflammation and autophagy in schizophrenia

European Journal of Pharmacology, Год журнала: 2025, Номер 997, С. 177469 - 177469

Опубликована: Март 5, 2025

Язык: Английский

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The Regulation of Cellular Senescence in Cancer

Biomolecules, Год журнала: 2025, Номер 15(3), С. 448 - 448

Опубликована: Март 20, 2025

Cellular senescence is a stable state of cell cycle arrest caused by telomere shortening or various stresses. After senescence, cells cease dividing and exhibit many age-related characteristics. Unlike the halted proliferation cells, cancer are considered to have unlimited growth potential. When display senescence-related features, such as loss stem failure, they can inhibit tumor development. Therefore, inducing enter serve barrier However, recent studies found that sustained normal under certain circumstances exert environment-dependent effects promotion inhibition producing cytokines. In this review, we first introduce causes characteristics induced cellular analyze process immune then discuss dual regulatory role on senescence-induced therapies targeting cells. Finally, in progression treatment opportunities, propose further therapy.

Язык: Английский

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Intracellular acidification and glycolysis modulate inflammatory pathway in senescent cells

The Journal of Biochemistry, Год журнала: 2024, Номер 176(2), С. 97 - 108

Опубликована: Апрель 2, 2024

Abstract Senescent cells accumulate in various organs with ageing, and its accumulation induces chronic inflammation age-related physiological dysfunctions. Several remodelling of intracellular environments have been identified senescent cells, including enlargement cell/nuclear size acidification. Although these alterations were reported to be involved the unique characteristics contribution acidification senescence-associated cellular phenotypes is poorly understood. Here, we that upregulation TXNIP paralog ARRDC4 as a hallmark addition KGA-type GLS1. These genes also upregulated response Neutralization acidic environment ameliorated not only senescence-related TXNIP, KGA but inflammation-related genes, possibly through suppression PDK-dependent anaerobic glycolysis. Furthermore, found expression acidification-induced ARRDC4, correlated inflammatory gene heterogeneous cell population vitro even vivo, implying pH features, such SASP.

Язык: Английский

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Recent Developments in Small-Molecule Fluorescent Probes for Cellular Senescence

Chemosensors, Год журнала: 2024, Номер 12(7), С. 141 - 141

Опубликована: Июль 15, 2024

Cellular senescence is a recently emerged research topic in modern biology. Often described as double-edged sword, it encompasses numerous essential biological processes, including beneficial effects such wound healing and embryonic development, well detrimental contributions to chronic inflammation tumor development. Consequently, there an increasing need unravel the intricate networks of develop reliable detection methods distinguish from related phenomena. To address these challenges, variety have been developed. In particular, small-molecule fluorescent probes offer distinct advantages suitability for real-time live cell monitoring vivo imaging, superior tunable properties, versatile applications. this review, we explored recent advancements development toward cellular by targeting various senescence-related These phenomena include upregulation senescence-associated enzymes, perturbation subcellular environment, increased endogenous ROS levels. Moreover, multi-senescence biomarker-targeting approaches are also discussed improve their sensitivities specificities senescence. With advances probe current challenges field facilitate further progress.

Язык: Английский

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Senescence in the ageing skin: a new focus on mTORC1 and the lysosome

FEBS Journal, Год журнала: 2024, Номер unknown

Опубликована: Сен. 26, 2024

Ageing is defined as the progressive loss of tissue function and regenerative capacity caused by both intrinsic factors i.e. natural accumulation damage, extrinsic damage from environmental stressors. Cellular senescence, in brief, an irreversible exit cell cycle that occurs primarily response to excessive cellular such ultraviolet (UV) exposure oxidative stress, it has been comprehensively demonstrated contribute organismal ageing. In this review, we will focus on skin, organ which acts essential protective barrier against injury, insults, infection. We explore evidence for existence contribution senescence skin discuss known molecular mechanisms driving with a dysregulation master growth regulator, mechanistic Target Rapamycin Complex 1 (mTORC1). interplay dysregulated mTORC1 lysosomes how they phenotypes.

Язык: Английский

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The syntaxin-binding protein STXBP5 regulates progerin expression

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Окт. 8, 2024

Hutchinson–Gilfor progeria syndrome (HGPS) is caused by a mutation in Lamin A resulting the production of protein called progerin. The accumulation progerin induces inflammation, cellular senescence and activation P53 pathway. In this study, through public dataset analysis, we identified Syntaxin Binding Protein 5 (STXBP5) as an influencing factor expression. STXBP5 overexpression accelerated onset senescence, while deletion suppressed expression, delayed senility, decreased expression senescence-related factors. have synergistic effects protein-protein interaction. Through bioinformatics found that affects ageing-related signalling pathways such mitogen-activated kinase (MAPK) pathway, hippo pathway interleukin 17 (IL17) progerin-expressing cells. addition, induced changes transposable elements (TEs), human endogenous retrovirus H internal coding sequence (HERVH-int) changes. Our coimmunoprecipitation (Co-IP) results indicated bound directly to Therefore, decreasing potential new therapeutic strategy for treating phenotypes patients with HGPS.

Язык: Английский

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CDK4/6 inhibitors promote senescence-associated lysosomal alterations and enhance sensitivity to lysosomotropic agents in breast cancer

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 23, 2024

Abstract Breast cancer is a leading cause of mortality worldwide. Pharmacological inhibitors Cyclin- Dependent Kinases (CDK) 4 and 6 (CDK4/6i) inhibit breast growth by inducing senescent-like state. However, the long-term treatment efficacy remains hindered development drug resistance. Clearance cells may extend durability treatment. In this study, we showed that CDK4/6i-treated exhibit various senescence-associated phenotypes, but remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, identified significantly increased lysosomal mass altered structure across cell types upon exposure CDK4/6i in preclinical systems clinical specimens. We demonstrated these alterations render sensitive lysosomotropic agents, such as L- leucyl-L-leucine methyl ester (LLOMe) salinomycin. Importantly, sequential with CDK4/6i/lysosomotropic agents effectively reduced both Hormone Receptor- positive (HR + ) triple-negative (TNBC) vivo. This therapeutic strategy offers promising approach eliminate CDK4/6i-induced senescent(-like) cells, potentially reducing tumor recurrence enhancing overall therapy.

Язык: Английский

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