Search Results (1,822)

Background: Rhabdoid tumor of the kidney (RTK) is a highly aggressive pediatric malignancy characterized by biallelic SMARCB1 loss, resulting in aberrant MYC pathway activation and cell cycle regulation. MYC-activated tumors are vulnerable in splicing functions and sensitive to splicing inhibitors. Therefore, in this study, cyclin-dependent kinase 11 (CDK11), which regulates both cell cycle and RNA splicing, was tested as a therapeutic target in RTK. Methods: CDK11A/B expression was analyzed using the TARGET-RT database. The therapeutic efficacy of the CDK11 inhibitor OTS964 was evaluated in two RTK cell lines (G401 and JMU-RTK-2) and a JMU-RTK-2 xenograft mouse model. Cytotoxicity, apoptosis, cell cycle, and RNA splicing were examined using the Sulforhodamine B assay, immunoblotting, flow cytometry, and RT-PCR. Results: CDK11B, but not CDK11A, was significantly upregulated in RTK and correlated with the poor survival. OTS964 inhibited RTK cell growth in vitro with the IC50 of 33.1 nM (G401) and 19.3 nM (JMU-RTK-2) and significantly prolonged survival in vivo (median survival: 46.5 vs. 37.0 days, p < 0.01) without marked toxicity. Mechanistically, OTS964 induced G2/M cell cycle arrest and p53 upregulation, disrupted RNA splicing via SF3B1 dephosphorylation, and ultimately led to apoptosis through caspase-3 activation. Conclusions: CDK11 inhibition by OTS964 effectively suppresses RTK growth through cell cycle arrest and RNA splicing inhibition, leading to apoptosis. OTS964 shows potent anti-tumor activity and tolerability, supporting CDK11 as a promising therapeutic target for RTK and related SMARCB1-deficient cancers. Full article

Estrogen receptor-positive (ER⁺) breast cancer represents the most prevalent molecular subtype of breast cancer, characterized by hormone-dependent growth, relatively indolent progression, and a pronounced tendency to metastasize to bone. While endocrine therapies remain the cornerstone of treatment, a significant proportion of ER⁺ tumors eventually develop resistance, culminating in distant metastases—most frequently to the bone. Bone metastasis substantially compromises patient survival and quality of life, highlighting the critical need to elucidate its molecular underpinnings. Recent multi-omics and mechanistic studies have shed light on the complex interplay between tumor-intrinsic signaling pathways, such as dysregulated ER signaling, PI3K/AKT/mTOR, TGF-β, and Hippo pathways, and the bone microenvironment, including osteoclast activation, immune suppression, and stromal remodeling. This review systematically summarizes the current understanding of the molecular mechanisms driving bone metastasis in ER⁺ breast cancer, with a particular focus on tumor–bone microenvironment crosstalk and key regulatory pathways. Additionally, we discuss recent advances in therapeutic strategies, encompassing next-generation endocrine therapies, CDK4/6 inhibitors, bone-targeted agents, and pathway-specific inhibitors. Together, these insights pave the way for more effective and personalized interventions against ER⁺ breast cancer with bone involvement. Full article

Background: Canine mammary carcinoma (CMC) is the most common malignant tumour in female dogs and, due to its similarities, is a valuable comparative model for human breast cancer. Kinase inhibitors have revolutionised the treatment of human breast cancer; their use in veterinary oncology remains marginal. Aim: This review summarises the current knowledge of kinase signalling pathways in CMC and assesses which kinase inhibitors approved for human use have potential in veterinary medicine. Methods: A systematic search of the PubMed database from 1985 to 2025 was performed, focusing on kinase-targeted therapies in both human and canine mammary carcinomas. Data were categorised according to molecular target, clinical approval status, and available preclinical or clinical veterinary evidence. Results: Key molecular pathways targeted by kinase inhibitors are conserved across species, supporting translational opportunities. In vitro studies demonstrate that palbociclib, alpelisib, everolimus, and lapatinib inhibit growth and signalling in CMC cell lines. Clinical trials have not been conducted. Conclusions: Approved kinase inhibitors for human use have untapped therapeutic potential in veterinary oncology. Translational research, including xenograft and organoid models, followed by clinical trials in dogs, is required. Gaining this knowledge could lead to targeted treatment for dogs while advancing comparative understanding of mammary cancer biology across species. Full article

Background/Objectives: Despite initial sensitivity to ET, most patients with HR+/HER2− breast cancer develop resistance. A key molecular mechanism of endocrine resistance in HR+ breast cancer involves dysregulation of the cyclin D–CDK4/6–Rb signaling axis, which controls the transition from the G1 to S phase of the cell cycle. Introducing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) has changed therapeutic paradigms in HR+/HER2− breast cancer, as their synergistic use with endocrine therapy significantly prolongs progression-free survival (PFS) and effectively mitigates clinically relevant endocrine resistance in this patient population compared to ET alone. The aim of our study was to evaluate patients’ clinical characteristics, the clinical effectiveness of treatment, measured by progression-free survival (PFS), and the safety profile of combined ribociclib (CDK4/6i) and standard endocrine therapy (aromatase inhibitor) as a first-line treatment for patients with HR+/HER2− advanced or metastatic breast cancer at the Clinic of Oncology, University Clinical Centre Nis, Serbia. Methods: In this study, we present a retrospective prospective analysis of all patients with metastatic HR+/HER2− breast cancer treated with a combination of ribociclib and aromatase inhibitors in the first-line treatment of metastatic HR+/HER2− BC between June 2022 and January 2025, with a follow-up completed in October 2025. A total of 132 patients who met the criteria were included. Results: The median progression-free survival (PFS) in the entire group was 30 months, while the 12-, 24-, and 36-month PFS were 82.15%, 72.24%, and 28.75%, respectively. The overall response rate (ORR) was 41.7%, while the clinical benefit rate (CBR) was 89.3%. There was no statistically significant difference in PFS with respect to tumor grade (p = 0.54), Ki 67 level (<20% vs. >20%, p = 0.83), or the type of adjuvant endocrine therapy used (tamoxifen vs. AI) It is important to emphasize that female patients who had not previously received chemotherapy had a better response to ribociclib compared to those who had (33 m vs. 28 m, p = 0.05). Although a numerical difference in PFS was found in patients with bone-only metastases compared to those with metastases in other organs, the difference was not statistically significant (PFS 33 m vs. 30 m, p = 0.27;), and efficacy was consistent across menopausal status groups. The most common adverse effect was neutropenia, occurring in 89.4% of patients, 47.7% of whom presented with grade 3 or 4. As for hepatotoxicity, transaminase increase occurred in 25 patients (18.8%), 5 of whom (3.8%) were grade 3–4, and QTc interval prolongation occurred in 5.3% of patients. Conclusions: The results in terms of PFS and AEs are consistent with those of pivotal studies and real clinical practice data, but a direct comparison is not possible due to differences in patient populations. Ribociclib once again demonstrated efficacy in all patient subgroups and remains the gold standard, alongside ET, for first-line HR+/HER2-negative mBC. Full article

Background/Objectives: Some patients initially diagnosed with non-high-risk neuroblastoma follow a high-risk clinical course and have poor survival compared to those initially diagnosed with high-risk neuroblastoma. We aimed to identify molecular aberrations present at diagnosis that may explain the high-risk clinical course in this patient group. Methods: Data were collected from non-high-risk neuroblastoma patients diagnosed at our center between 2014 and 2021. Segmental chromosomal aberrations (SCAs), gene amplifications and mutations at diagnosis were detected by a single-nucleotide polymorphism array and next-generation sequencing. Telomere maintenance mechanisms (TMMs) were investigated using fluorescent in situ hybridization, whole genome sequencing (WGS) and RNA sequencing. SCA counts were imputed by using multiple imputation. Results: The total cohort included 89 patients. Thirteen patients developed a high-risk clinical course (group A) due to progression (n = 4), local relapse (n = 4), refractory disease (n = 3) or metastases (n = 2). Seventy-six patients followed a non-high-risk clinical course (group B). An SCA profile (≥1 SCA) was present in 76% of patients in group A and only 15% in group B (p = 0.004). 1p deletion was associated with a high-risk clinical course (p = 0.034). Gains of 1q, 2p and 17q, and deletions of 4p and 11q were more common in group A. After imputation, SCA count was associated with a high-risk clinical course (pooled OR 1.256 with 95% CI 1.006–1.568, p = 0.044). Two patients, both group A, exhibited MDM2/CDK4 amplification. Alternative lengthening of telomeres (ALT) was activated in 57% of group A. Conclusions: SCA profile and 1p deletion are associated with a high-risk clinical course. ALT activation, MDM2/CDK4 co-amplification, SCA count, gains of 1q, 2p, and 17q, and deletions of 4p and 11q may also be relevant molecular markers. Larger studies are needed for confirmation of these findings. Full article

Background: Advances in the understanding of molecular mechanisms of human diseases, along with the generation of large amounts of molecular datasets, have highlighted the variability between patients and the need to tailor therapies to individual characteristics. In particular, RNA-based therapies hold strong promise for new drug development, as they can be easily designed to target specific molecules. Gene and protein functions, however, operate within a highly interconnected network, and inhibiting a single function or repressing a single gene may lead to unexpected secondary effects. In this study, we focused on genes associated with Alzheimer’s disease, a progressive neurodegenerative disorder characterized by complex pathological processes leading to cognitive decline and dementia. Its hallmark features include the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Methods: We built a protein interaction network subgraph seeded on five Alzheimer’s-associated genes, including tau and amyloid-β precursor, and integrated it with microRNAs in order to select regulated nodes, study the effects of their depletion on signaling pathways, and prioritize targets for microRNA-based therapeutic approaches. Results: We identified nine protein nodes as potential candidates (Pik3R1, Bace1, Traf6, Gsk3b, Akt1, Cdk2, Adam10, Mapk3 and Apoe) and performed in silico node depletion to simulate the effects of microRNA regulation. Conclusions: Despite intrinsic limitations of the approach, such as the incompleteness of the available information or possible false associations, the present work shows clear potential for drug design and target prioritization and underscores the need for reliable and comprehensive maps of interactions and pathways. Full article

Background: This study systematically investigates the therapeutic effects of naringenin (NAR) and oleuropein (OLE) on prostate cancer through miR-155-5p regulation. Methods: Experimental studies conducted on MAT-LyLu prostate cancer cell lines revealed that the application of NAR (50 μM) and OLE (75 μM) significantly increased miR-155-5p expression by 2.89-fold and 1.74-fold, respectively (p < 0.05). Bioinformatics analyses have indicated that miR-155-5p interacts with critical oncogenic pathways such as KRAS, CDK2, NF-κB, and TGF-β/Smad2. Computational analyses have revealed that miR-155-5p interacts with 16 critical oncogenic targets, including KRAS and CDK2. Molecular docking studies showed that NAR binds to the Switch I/II region of KRAS with a binding energy of −8.2 kcal/mol, while OLE binds to the ATP-binding pocket of CDK2 with an affinity of −9.1 kcal/mol. Pharmacokinetic evaluations revealed that NAR indicated high oral bioavailability (93.763% HIA) and full compliance with Lipinski’s rules, while OLE required advanced formulation strategies due to its high polarity. Network pharmacology analyses have shown that NAR affects lysosomal functions and enzyme regulation, while OLE affects G protein-coupled receptors and oxidoreductase activity. Results: Results indicate that NAR and OLE exhibit antitumor effects through multiple mechanisms by increasing miR-155-5p expression and inhibiting critical oncogenic targets in prostate cancer. Conclusion: Findings suggest that the dietary intake of these natural compounds (citrus and olive products) should be considered in prostate cancer prevention strategies, shedding light on the epigenetic mechanisms of polyphenols in cancer treatment and contributing to the development of new therapeutic strategies. Full article

Thalamic gliomas are among the most challenging pediatric brain tumors due to the delicate functions of the thalamus. Limited surgical intervention leads to the use of adjuvant therapies, including targeted therapy. Thalamic gliomas can be divided into two distinct groups: diffuse midline glioma (DMG) and low-grade glioma (LGG). The most common mutations that can be targeted for treatment are the KIAA1549-BRAF fusion; BRAF V600E mutation; EGFR, FGFR, PDGFR, NTRK, and CDK4/6 mutations; other MAP kinase pathway alterations; and PI3K/AKT/mTOR activation. The bithalamic high-grade glioma especially demonstrates EGFR mutations which makes it a distinct entity. Targeted therapy, including tyrosine kinas inhibitors has been shown to improve the overall survival compared to conventional therapy in certain situations. Demonstrating the mutation carried by the tumor is very critical in this regard. The purpose of this article is to focus on the treatment of thalamic glioma in pediatric patients in light of molecular information. Full article

Background: In malignant pleural mesothelioma, epithelioid histology is traditionally considered a favorable prognostic marker. However, it remains clinically undetermined whether the intensity of an oncogenic insult can disrupt this link. Radiation-induced cases serve as an unconfounded biological model to dissect such trajectories masked by asbestos confounding. Methods: We performed an Individual Patient Data (IPD) synthesis of 20 strictly asbestos-unexposed human cases, applying clinically established dose stratification (intermediate: 20–45 Gy vs. high: >45 Gy). To confirm the observed pattern, we examined data from 829 dogs in the Colorado State University (CSU) Beagle Study. Results: In the intermediate-dose group (n = 13), a significant positive correlation persisted between age at radiotherapy and the latent period (ρ = 0.567, p = 0.043). Conversely, high-dose exposure (>45 Gy) showed a disruption of this age-dependent pattern, with a trend toward inverse correlation (ρ = −0.754, p = 0.084). Interaction analysis confirmed a statistically significant divergence between these dose-dependent trends (p = 0.005). The CSU Beagle Study (n = 829) demonstrated the physical basis of this phenomenon: in the canine model, high-dose exposure (≥0.74 Gy) triggered a “Step-Jump” in cumulative incidence (30.4% at 0.5 years), indicating instantaneous carcinogenic onset distinct from cumulative biological aging. Conclusions: This kinetic divergence points to a “Diagnostic Trap.” We propose a ‘Single- to Double-Brake’ framework where intermediate doses preserve age-dependent progression, whereas high doses likely trigger catastrophic genomic failure (chromothripsis) that bypasses the time required for morphological dedifferentiation. Consequently, morphologically indolent epithelioid tumors in high-dose survivors may harbor aggressive molecular profiles not predicted by histology alone, necessitating risk-stratified precision surveillance. Full article

Non-coding RNAs (ncRNAs) have emerged as promising biomarkers for prostate cancer (PCa), yet evidence remains dispersed across heterogeneous studies and their regulatory context is seldom analyzed in an integrated manner. This study systematically maps ncRNAs reported as diagnostic biomarkers for PCa and characterizes their molecular interactions through in silico analyses. A comprehensive evidence-mapping strategy across major bibliographic databases identified 693 studies, of which 58 met eligibility criteria. Differentially expressed ncRNAs were extracted and classified by RNA type. Subsequently, miRNA–target prediction, miRNA–protein interaction network construction, and functional enrichment analyses were performed to explore the regulatory landscape of miRNA-associated proteins. Results: The final dataset included 4500 participants (2871 PCa cases and 2093 controls) and reported 94 differentially expressed miRNAs, eight lncRNAs, and several circRNAs, snoRNAs, snRNAs, and piRNAs. In silico analyses predicted 13,493 miRNA–mRNA interactions converging on 4916 unique target genes, with an additional 2481 prostate tissue-specific targets. The miRNA–protein network comprised 845 nodes and 2335 edges, revealing highly connected miRNAs (e.g., hsa-miR-16-5p, hsa-miR-20a-5p) and protein hubs (QKI, YOD1, TBL1XR1; prostate-specific CDK6, ACVR2B). Enrichment analysis showed strong overrepresentation of metabolic process-related GO terms and cancer-associated KEGG pathways. Conclusions: These findings refine the list of promising ncRNA biomarkers and highlight candidates for future clinical validation. Full article

Background/Objectives: Sex-specific differences in the mechanisms of acute liver injury remain poorly understood. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) is crucial for liver development and endoplasmic reticulum (ER) homeostasis. This study aimed to investigate sex-dependent changes in CDK5RAP3 expression in a carbon tetrachloride (CCl₄)-induced acute liver injury model and to explore the mechanisms underlying differential susceptibility between males and females. Methods: Acute liver injury was induced in male and female mice by CCl₄ administration. Liver injury was evaluated by serum biochemical parameters and histopathological analysis. CDK5RAP3 expression, inflammatory cytokines, and ER stress-related apoptotic markers were assessed. Hepatocyte apoptosis was examined by TUNEL staining. In addition, CDK5RAP3 was conditionally deleted in mouse embryonic fibroblasts (MEFs) using 4-hydroxytamoxifen to assess its direct role in regulating inflammatory and apoptotic responses in vitro. Results: CCl₄ exposure caused liver injury in both sexes, with male mice showing more severe biochemical and histological damage. CDK5RAP3 expression was significantly reduced after CCl₄ treatment, particularly in males. Inflammatory mediators and ER stress-associated apoptotic markers were upregulated, accompanied by increased hepatocyte apoptosis. A similar enhancement of inflammatory and apoptotic signaling was observed in CDK5RAP3-deficient MEFs. Conclusions: Downregulation of CDK5RAP3 is associated with ER stress, inflammation, and apoptosis, contributing to increased susceptibility of male mice to acute liver injury. These findings provide insight into sex-specific mechanisms of hepatic injury and highlight CDK5RAP3 as a potential therapeutic target. Full article

Background: Non-small-cell lung cancer (NSCLC) remains a major therapeutic challenge due to its high incidence and mortality. Herba Patriniae (HP), a traditional Chinese medicine, has long been used for respiratory disorders and exhibits anti-cancer potential. However, the therapeutic effects of HP on NSCLC and the underlying mechanisms have not been fully elucidated. Methods: Network pharmacology was applied to identify the core active components of HP and their potential targets in NSCLC. The anti-cancer effects of the core HP component Linarin on the malignant phenotypes of NSCLC cells were characterized using Tumor Protein P53 (p53) wild-type A549 and p53-null H1299 cell lines with Cell Counting Kit-8 (CCK-8), EdU fluorescence staining, colony formation, apoptosis analysis, cell cycle analysis, and senescence-associated β-galactosidase (SA-β-gal) staining, together with molecular docking and Western blotting analyses. Results: Network pharmacology analysis identified Linarin as the core active component of HP and screened out six hub targets, including Cyclin Dependent Kinase 1/4 (CDK1/4), Cyclin A2/B1 (CCNA2/B1), and Checkpoint Kinase 1/2 (CHEK1/2), which were found to be mainly enriched in cell cycle and senescence pathways. In vitro assays showed that Linarin dose-dependently (0–200 μM) inhibited NSCLC cell proliferation, induced G0/G1 phase arrest, and promoted cellular senescence and apoptosis in both cell lines, irrespective of p53 status. Molecular docking confirmed strong binding affinities between Linarin and the hub targets, and Western blotting confirmed that Linarin downregulated CCNA2/B1 and CHEK1. Conclusions: This study demonstrates that Linarin, the core active component of HP, exerts potent anti-NSCLC effects by inducing G0/G1 arrest, senescence, and apoptosis. These effects are associated with the downregulation of key cell cycle regulators, including CCNA2/B1 and CHEK1. Together, these findings highlight the potential of Linarin as a promising therapeutic option for NSCLC. Full article

Testosterone (T) produced by Leydig cells (LCs) is essential for male reproduction; yet, the regulatory mechanisms underlying steroidogenesis remain incompletely understood. Here, we investigated the role of cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) in Leydig cell development and steroidogenesis, based on its identification by immunoprecipitation-mass spectrometry (IP-MS) as a protein associated with steroidogenesis and cholesterol metabolism in mouse testicular tissue. Using human samples, we found that CDK5RAP3 expression was significantly reduced in Leydig cells from patients with spermatogenic failure (T < 10.4 nmol/L). Notably, CDK5RAP3 expression increased during mouse postnatal Leydig cell maturation and regeneration in an ethane dimethanesulfonate (EDS)-induced rat model. Functional analyses in primary LCs and MLTC-1 cells showed that hCG stimulation triggered CDK5RAP3 nuclear translocation without altering its overall expression, while CDK5RAP3 knockdown markedly impaired hCG-induced testosterone production and reduced the expression of the steroidogenic regulator steroidogenic acute regulatory (STAR) protein, as well as key steroidgenic enzymes, including cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 17a-hydroxylase (CYP17A1), and 3β-hydroxysteroid dehydrogenase (HSD3B). Conversely, CDK5RAP3 overexpression enhanced testosterone production in the absence of hCG. In vivo, AAV2/9-mediated CDK5RAP3 silencing in adult mouse testes resulted in a significant reduction in serum testosterone levels compared with controls (3.60 ± 0.38 ng/mL vs. 1.83 ± 0.37 ng/mL). Mechanistically, CDK5RAP3 interacted with SMAD4 and CEBPB, and BMP pathway inhibition by Noggin rescued the testosterone deficit caused by CDK5RAP3 loss. Together, these findings identify CDK5RAP3 as an essential regulator of Leydig cell steroidogenesis and provide insight into its potential relevance to male infertility associated with low testosterone. Full article

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for estrogen receptor-positive (ER+) breast cancer, yet resistance remains a major clinical challenge. Although CDK4/6i induce G₁ arrest and therapy-induced senescence (TIS), the exact nature of this senescent state and its contribution to resistance are not well understood. To explore this, we developed palbociclib- (2PR, 9PR, TPR) and abemaciclib- (2AR, 9AR, TAR) resistant ER+ breast cancer sublines through prolonged drug exposure over six months. Resistant cells demonstrated distinct phenotypic alterations, including cellular senescence, reduced mitochondrial membrane potential, and impaired glycolytic activity. Cytokine profiling and enzyme-linked immunosorbent assay (ELISA) validation revealed a non-canonical senescence-associated secretory phenotype (SASP) characterized by elevated growth/differentiation factor 15 (GDF-15) and serpin E1 (plasminogen activator inhibitor-1, PAI-1) and absence of classical pro-inflammatory interleukins, including IL-1α and IL-6. IL-8 levels were significantly elevated, but no association with epithelial–mesenchymal transition (EMT) was observed. Resistant cells preserved their epithelial morphology, showed no upregulation of EMT markers, and lacked aldehyde dehydrogenase 1-positive (ALDH1+) stem-like populations. Additionally, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) was strongly upregulated in palbociclib-resistant cells. Together, these findings identify a distinct, non-canonical senescence phenotype associated with CDK4/6i resistance and may provide a foundation for identifying new vulnerabilities in resistant ER+ breast cancers through targeting SASP-related signaling. Full article

Cervical cancer (CC) remains a common malignant tumor that seriously threatens women’s health globally. Gramine (GR), a natural alkaloid derived from plants such as Arundo donax L., exhibits anti-tumor activities, yet its mechanistic actions in CC are still unclear. Here, we integrated cell-based assays, network pharmacology, and multi-omics analysis to systematically investigate the molecular mechanisms underlying GR’s anti-CC effects. In vitro experiments showed that GR significantly inhibited proliferation and migration, induced apoptosis, and triggered G₀/G₁ phase cell cycle arrest in HeLa cells. Integrated multi-omics analysis identified CDK2 as a critical target of GR, with both mRNA and protein levels markedly reduced following treatment. Mechanistically, GR likely suppresses CC progression by modulating the “CYP4A22-AS1/LINC00958–hsa-miR-133b–CDK2” competitive endogenous RNA (ceRNA) axis. Immune analysis indicated positive correlations of CDK2, CYP4A22-AS1, and LINC00958 with the immune checkpoint molecule CD47. Collectively, our findings demonstrate that GR inhibits CC through a ncRNA-mediated suppression of CDK2, leading to reduced HeLa cell proliferation and migration and enhanced apoptosis. These results provide a mechanistic rationale for developing GR as a candidate agent for targeted therapy and immuno-combination strategies in CC. Full article