Molecular Cell, Journal Year: 2024, Volume and Issue: 84(23), P. 4483 - 4485
Published: Dec. 1, 2024
Language: Английский
Life, Journal Year: 2025, Volume and Issue: 15(1), P. 126 - 126
Published: Jan. 18, 2025
Post-translational modifications (PTMs) of proteins dynamically build the buffering and adapting interface between oncogenic mutations environmental stressors, on one hand, cancer cell structure, functioning, behavior. Aberrant PTMs can be considered as enabling characteristics long they orchestrate all malignant variability in proteome cells, cancer-associated tumor microenvironment (TME). On other enhance anticancer mechanisms tumoral ecosystem or sustain beneficial effects oncologic therapies through degradation inactivation carcinogenic or/and activation tumor-suppressor proteins. In this review, we summarized analyzed a wide spectrum involved regulatory that drive tumorigenesis, genetic instability, epigenetic reprogramming, events metastatic cascade, cytoskeleton extracellular matrix (ECM) remodeling, angiogenesis, immune response, tumor-associated microbiome, metabolism rewiring most important hallmarks cancer. All develop due to proteins, which modulate gene transcription, intracellular signaling, protein size, activity, stability localization, trafficking, secretion, half-life, protein–protein interactions (PPIs). associated with exploited better understand underlying molecular heterogeneous chameleonic disease, find new biomarkers progression prognosis, personalize oncotherapies, discover targets for drug development.
Language: Английский
Citations
2
Advanced Science, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 14, 2025
Abstract The current treatment of triple‐negative breast cancer (TNBC) is still primarily based on platinum‐based chemotherapy. However, TNBC cells frequently develop resistance to platinum and experience relapse after drug withdrawal. It crucial specifically target eliminate cisplatin‐tolerant administration. Here, it reported that upregulated N 6 ‐methyladenosine (m A) modification drives the development in during cisplatin treatment. Mechanistically, histone deacetylase 2 (HDAC2) mediates delactylation methyltransferase‐like 3 (METTL3), facilitating METTL3 interaction with Wilms’‐tumor‐1‐associated protein subsequently increasing m A transcript‐associated DNA damage repair. This ultimately promotes cell survival under cisplatin. Furthermore, pharmacological inhibition HDAC2 using Tucidinostat can enhance sensitivity therapy. study not only elucidates biological function lactylated tumor but also highlights its negative regulatory effect resistance. Additionally, underscores nonclassical functional mechanism as a HDAC inhibitor for improving efficacy against TNBC.
Language: Английский
Citations
2
Clinical Science, Journal Year: 2025, Volume and Issue: 139(02), P. 151 - 169
Published: Jan. 1, 2025
Lactylation, a post-translational modification, has been linked to gene transcription regulation through epigenetic modulation in various pathophysiological processes. The lactylation regulatory proteins, known as writers, erasers, and readers, govern their dynamics by adding, removing, recognizing lactyl groups on proteins. Macrophages, cells of the immune system, maintain homeostasis, responding dynamically diverse internal external stimuli. Emerging researches unveil that lactylation, inducing macrophage activation polarization, affects functionality pathological conditions such inflammation, tumor microenvironment, fibrosis. Evidence progressively indicates lactate-driven alterations levels within macrophages can influence pathogenesis numerous diseases. This review aims systematically summarize research progress macrophages, explore its functions mechanisms which contributes pathology different disease phenotypes, propose future directions along with potential diagnostic therapeutic strategies.
Language: Английский
Citations
1
Theranostics, Journal Year: 2025, Volume and Issue: 15(6), P. 2338 - 2359
Published: Jan. 13, 2025
Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous checkpoints, particularly those within B7 family. Elucidating mechanisms that govern induction family molecules is crucial for advancement immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, suggested may play role in reshaping tumor microenvironment and facilitating evasion. Methods: We analyzed glycolysis pathway's enrichment patients with immune-evading tumors assessed impact lactate treatment on antitumor immunity CD8+ T microenvironment. interrupted using dehydrogenase A (LDHA) knockdown sodium oxamate, evaluated its effects cell cytotoxicity. Additionally, we investigated correlation between B7-H3 expression pathway, explored molecular underlying lactate-induced expression. Results: Our findings revealed pathway was highly enriched tumors. Lactate inhibited cells, whereas interruption via LDHA or oxamate augmented cytotoxicity effectively counteracting found be closely linked pathway. Mechanistically, lactate-upregulated H3K18la directly bound promoter conjunction transcription factor Creb1 co-activator Ep300, leading increased contributing progression by compromising proportion tumor-infiltrating cells. In mouse bearing models, inhibiting suppressed growth, activated demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced efficacy anti-PD-1 treatment. Conclusions: This study uncovers novel mechanism which modulates through expression, providing new avenues metabolism-targeted
Language: Английский
Citations
1
Biomolecules, Journal Year: 2024, Volume and Issue: 14(12), P. 1646 - 1646
Published: Dec. 21, 2024
Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of Warburg effect, contribute to suppression through CD8+ T cell functionality by promoting regulatory (Treg) activity. Lactylation, post-translational modification (PTM), alters histone non-histone proteins, influencing gene expression further reinforcing suppression. In complex TME, are not only associated with but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes dual lactylation immunity, analyzing how these factors evasion, therapeutic resistance, activation. Furthermore, article highlights emerging strategies aimed at inhibiting production or disrupting pathways achieve balanced regulation effects. These offer new insights into overcoming tumor-induced hold potential improve efficacy immunotherapies.
Language: Английский
Citations
4
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 3, 2025
ABSTRACT Oncogenes hyperactive lactate production, but the mechanisms by which facilitates tumor growth are unclear. Here, we demonstrate that is essential for nucleotide biosynthesis in pediatric diffuse midline gliomas (DMGs). The oncogenic histone H3K27M mutation upregulates phosphoglycerate kinase 1 (PGK1) and drives production from [U- 13 C]-glucose DMGs. Lactate activates nucleoside diphosphate NME1 via lactylation promotes synthesis of triphosphates proliferation. Importantly, show this mechanistic link between glycolysis provides a unique opportunity deuterium metabolic imaging Spatially mapping 2 H-lactate [6,6- H]-glucose allows visualization metabolically active lesion an early readout response to standard-of-care radiation targeted therapy precedes extended survival reflects pharmacodynamic alterations at tissue level preclinical DMG models vivo clinical field strength (3T). In essence, have identified H3K27M-lactate-NME1 axis proliferation non-invasive STATEMENT OF SIGNIFICANCE This study establishes role driving glucose using DMI clinically relevant models. Our studies lay foundation precision patients.
Language: Английский
Citations
0
Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1787 - 1821
Published: Jan. 2, 2025
Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles different aspects of energy metabolism signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as novel posttranslational modification (PTM). Research indicates that Kla essential balancing mechanism variety organisms involved many biological processes pathways. closely related to disease development represents potential important new drug target. In line with existing reports, we searched for newly discovered sites on histone nonhistone proteins; reviewed the mechanisms (particularly focusing enzymes directly reversible regulation Kla, including "writers" (modifying enzymes), "readers" (modification-binding "erasers" (demodifying enzymes); summarized crosstalk between PTMs help researchers better understand widespread distribution diverse functions. Furthermore, considering "double-edged sword" role both pathological contexts, this review highlights "beneficial" states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) "detrimental" pathogenic or inducive effects processes, particularly malignant tumors complex nontumor diseases. We also clarify molecular health disease, discuss feasibility therapeutic Finally, describe detection technologies their applications diagnosis clinical settings, aiming provide insights treatment diseases accelerate translation from laboratory research practice.
Language: Английский
Citations
0
Sensors, Journal Year: 2025, Volume and Issue: 25(4), P. 1045 - 1045
Published: Feb. 10, 2025
Lactate is a key metabolite in cellular respiration, and elevated levels usually indicate tissue hypoxia or metabolic dysregulation. The real-time detection of lactate particularly important situations such as exercise, shock, severe trauma, injury. Conventional assays are insufficient to address today’s complex variable testing environments, thus, there an urgent need for highly sensitive biosensors. This review article provides overview the concept composition electrochemical biosensors, well their recent advances. Comparisons popular studies on enzymatic non-enzymatic sensors, surface-related materials used modifications methods commonly sensors discussed separately. In addition, advances implantable non-implantable miniaturized discussed, emphasizing application continuous monitoring. Despite potential, challenges non-specific binding, biomaterial interference, biorecognition element stability issues remain during practical applications. Future research should aim improve sensor design, biocompatibility, integration with advanced signal processing techniques. With continued innovation, expected revolutionize personalized medicine, helping clinicians increase treatment efficiency experience use.
Language: Английский
Citations
0
Biomolecules, Journal Year: 2025, Volume and Issue: 15(3), P. 344 - 344
Published: Feb. 27, 2025
PHI-1, encoded by PPP1R14B, regulates cellular protein phosphatase-1 (PP1) signaling and has emerged as both a biomarker therapeutic target. Initially identified phospholipase-neighboring gene (PNG), PHI-1 is now known for its phosphorylation-dependent inhibition of PP1 holoenzymes, with bi-directional roles depending on expression levels. Under physiological conditions, selectively activity to maintain homeostasis, whereas pathological upregulation promotes oncogenic pathways, stabilizes tumor-promoting proteins, modulates immune responses. This article explores PHI-1’s emerging role pan-cancer in parallel emphasizing functions networks, smooth muscle contraction, cytoskeletal dynamics, selective proteostasis. The mechanistic insights highlight potential precision oncology, offering opportunities developing diagnostics therapies that target conditional functions.
Language: Английский
Citations
0
Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)
Published: March 8, 2025
Cancer remains the leading cause of mortality worldwide, and emergence drug resistance has made identification new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct glycolysis with limited ATP-producing capacity, recently gained recognition critical signaling molecule. It plays key role not only in cancer cell metabolism but also shaping tumor microenvironment (TME). Histone lysine lactylation, newly identified post-translational modification, been shown to influence range cellular processes cancer. Current research focuses on mechanisms functions histone lactylation cancer, including its gene expression regulation, signal transduction, protein synthesis. However, despite these advancements, there are still plenty barriers quest unravel modification. The single-cell spatial transcriptomics may offer valuable insights for selecting targets. This review provides comprehensive summary applications modification clinical settings. Through detailed analysis, we identify challenges limitations that exist current landscape. These lay groundwork future studies by highlighting promising directions.
Language: Английский
Citations
0