Search Results (6,062)

Magnetic fields (MFs) represent an emerging modality in cancer therapy, encompassing static, low-frequency, pulsed, and nanoparticle-mediated alternating fields. These interventions have demonstrated the capacity to modulate proliferation, apoptosis, ferroptosis, migration, and epithelial-to-mesenchymal transition (EMT) in tumor cells, often through reactive oxygen species (ROS) modulation, ion channel regulation, membrane receptor dynamics, and lysosomal membrane permeabilization. Magnetic nanoparticle hyperthermia (MHT) has reached clinical application, showing promising outcomes in glioblastoma and prostate cancer, while pulsed electromagnetic fields (PEMFs) and magneto-mechanical approaches are under preclinical investigation. The mechanistic diversity of MFs allows synergistic combination with chemotherapy, radiotherapy, and immunotherapy. However, parameter sensitivity, field standardization, and long-term safety remain challenges. Here, we review mechanistic insights, signaling pathways, and experimental and clinical evidence for MF-based cancer therapies, highlighting translational potential and the need for rigorous optimization to realize clinical efficacy. Full article

Aberrant expression of multiple microRNAs has been reported in gastric cancer. In particular, microRNA-597 has been associated with poor survival rates but is not yet well characterized. Seventy-five clinical samples, four cell lines, and two patient-derived organoids were evaluated for the expression of microRNA-597 and its target genes. microRNA-597 was transiently transfected for analysis of cell migration, invasion, wound healing, colony formation, and cell viability, and its regulation by long non-coding RNAs was explored using the TCGA-STAD and LncBook tools. In clinical samples, low expression of microRNA-597 was associated with the intestinal subtype (p = 0.002) and stages III and IV (p = 0.048). All functional readouts were reduced after microRNA-597 transfection, including colony formation, in patient-derived organoids. Among target genes, RUNX1 was directly regulated by microRNA-597. Other cell invasion genes were dependent on RUNX1 as a hub for regulation. Analysis of the Intersection between long non-coding RNAs co-expressed with RUNX1 and those with the highest microRNA-597 prediction binding identified KCNQ1OT1 as the top transcript. Silencing of KCNQ1OT1 and co-expression in clinical samples suggest the existence of a KCNQ1OT1/microRNA-597/RUNX1 network. The results indicate that microRNA-597 directly suppresses RUNX1, while KCNQ1OT1 modulates this interaction. Our approach enabled the simultaneous analysis of dysregulation in three families of transcripts in gastric cancer progression. Full article

Melanoma is the most aggressive type of skin cancer, driven by early invasion, phenotypic plasticity, and frequent resistance to targeted therapies. Although genomic profiling informs treatment selection, genotype alone often fails to predict therapeutic response, underscoring the need for rapid and physiologically relevant functional testing platforms. Here, we present a three-dimensional melanoma–skin organoid (mSO) model that integrates primary skin cells with melanoma cell lines in a self-assembling, high-throughput format. The spherical mSOs recapitulate native human skin architecture, including a stratified epidermis and a dermal–hypodermal core, while supporting melanoma growth within an appropriate tissue microenvironment. In this niche, melanoma cells display epidermal spreading in radial growth-like patterns, outward invasion, and transcriptional shifts toward a pro-invasive phenotype. Using live confocal imaging coupled with a custom automated image analysis pipeline, we quantitatively measured tumor growth, migration beyond the organoid boundary, and interactions between melanoma cells and normal melanocytes. The mSOs also captured genotype-specific drug responses: BRAF-mutant melanoma cells were sensitive to BRAF and MEK inhibition, whereas NRAS-mutant, BRAF–wild-type cells were resistant to BRAF inhibition but remained responsive to MEK inhibition. Altogether, our mSO platform combines architectural and functional complexity with experimental scalability, providing a robust framework for modeling melanoma progression and evaluating targeted therapeutic responses within a relevant skin microenvironment. In the future, adaptation of this system to include patient-derived tumor cells could support personalized therapeutic decision-making in melanoma. Full article

Background/Objectives: Vernodalin (VD) and crude extracts from Gymnanthemum extensum leaves have previously demonstrated anticancer activity; however, their underlying molecular effects remain incompletely understood. This study investigated the anticancer activities of VD and G. extensum extracts and characterized their associated molecular responses in breast (MDA-MB-231) and ovarian (A2780) cancer cells. Methods:G. extensum leaves were extracted with dichloromethane and ethyl acetate to obtain DEGE and EAGE, respectively. VD was isolated from EAGE and characterized by ¹H-NMR and HPLC. Phytochemical profiles of the extracts were analyzed by GC-MS and HPLC. Cytotoxicity, clonogenic survival, cell cycle progression, migration, and protein expression were evaluated using MTT assay, colony formation assay, flow cytometry, wound healing assay, and Western blotting. Results: GC–MS analysis revealed distinct phytochemical compositions between DEGE and EAGE, although both extracts contained high levels of neophytadiene and phytol. VD, DEGE, and EAGE inhibited cell proliferation and migration in both cancer cell lines. VD suppressed proteins associated with cancer progression, including SMYD3, BRAF, MELK, FOXM1, Cyclin B1, MDR1/ABCB1, and MMP-9, with molecular responses differing between MDA-MB-231 and A2780 cells. DEGE and EAGE exhibited molecular regulatory patterns distinct from those of purified VD, suggesting contributions from multiple phytochemical constituents. Conclusions: VD and G. extensum crude extracts exhibit significant in vitro anticancer activity against breast and ovarian cancer cells and induce distinct molecular responses. The differential effects of DEGE and EAGE may be attributable to differences in their phytochemical constituents. Full article

Melanoma is a highly aggressive and metabolically adaptable cancer that often resists conventional therapies. Targeting core bioenergetic pathways may, therefore, represent an effective strategy to improve therapeutic responses, particularly in tumors dependent on mitochondrial function. SC18 is an imidazolidine-2,4-dione compound that binds the NADH-binding pocket of voltage-dependent anion channels (VDACs), inducing mitochondrial dysfunction. VDAC expression is increased in melanoma and strongly associated with advanced disease stage and poor prognosis. In this study, we evaluated the effects of SC18 in melanoma cell lines with distinct pigmentation states, including melanin-rich melanotic human MNT-1 and mouse B16-F1, as well as low/amelanotic human SKMel28 and mouse YUMM cells. VDAC1, VDAC2 and VDAC3 were highly expressed across these melanoma lines, all of which relied on both glycolysis and mitochondrial oxidative phosphorylation for ATP production. SC18 reduced mitochondrial membrane potential and oxygen consumption rates, accompanied by declines in intracellular ATP levels and TCA cycle substrate utilization. SC18 also increased reactive oxygen species, mitochondrial superoxide, and lipid peroxidation, indicating enhanced oxidative stress. These metabolic and redox disturbances were associated with reduced cell viability and significantly impaired migration in multiple melanoma cell lines, supporting a potential anti-metastatic effect. In addition, SC18 showed synergistic cytotoxicity when combined with other chemotherapeutic agents. Overall, SC18 disrupted mitochondrial metabolism, induced oxidative stress, and impaired survival and motility pathways, with more pronounced effects in low/amelanotic than in melanotic melanoma cells. Together, these findings support the further development of SC18 as a mitochondrial metabolic disruptor that targets redox vulnerabilities in melanoma. Full article

Background/Objectives: Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, driven by invasive behavior and frequent resistance to systemic therapies. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) benefit patients with EGFR-mutant NSCLC, but their efficacy is often limited by tumor-intrinsic and environmental resistance mechanisms. Benzo[a]pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon from tobacco smoke, combustion, and dietary sources, is a known carcinogen; however, its role in modulating therapeutic responses is poorly understood. Studies, including ours, implicate the platelet-activating factor-receptor (PAFR) pathway in mediating environmental pollutant and therapy-induced effects on tumor growth and microvesicle particle (MVP) release. We hypothesized that PAFR activation mediates BaP-induced NSCLC progression and influences EGFR-TKI responses. Methods: We assessed the effects of BaP, PAFR agonist CPAF, EGFR-TKIs, and their combinations on cell viability, proliferation, migration, anchorage-independent growth, and MVP secretion. Results: BaP did not alter cell survival but significantly increased migration, growth, colony formation, and MVP release, similar to CPAF, and these effects were blocked by a PAFR antagonist or acid sphingomyelinase inhibitor. Notably, BaP did not significantly reduce EGFR-TKI efficacy at tested concentrations. Conclusions: These results show that environmental carcinogens modulate NSCLC behavior through PAFR signaling without compromising EGFR-TKI responsiveness, highlighting PAFR as a potential therapeutic target. Full article

Melanoma is a highly aggressive and invasive form of skin cancer that arises from the uncontrolled growth of melanocytes. It is characterized by early spread through the lymphatic system and metastasis. The success of metastasis is linked to the ability of melanoma and other cancer cells to resist anoikis, a type of cell death that occurs when cells lose their adhesion to the extracellular matrix. Redox signaling plays an essential role in anoikis resistance. The balance between intracellular levels of nitric oxide (NO) and the reactive oxygen species (ROS) O₂⁻ and H₂O₂ stimulate signaling pathways related to proliferation and survival or cell death. A375 and SK-MEL-28 human melanomas cell lines, representing primary melanoma and lymph node metastatic melanoma cells, respectively, under suspension and adherent culture conditions were used to investigate the redox regulation of anoikis resistance. Both cell lines express the three isoforms of nitric oxide synthases (NOS) and NADPH oxidase 4 (NOX4) as endogenous sources of NO and ROS, respectively. When A375 cells in suspension were treated with the pan-NOS inhibitor L-NAME, their viability decreased. The treatment resulted in a decrease in FAK phosphorylation at Tyr397 and in ERK 1/2 phosphorylation. The expression of FAK, ERK 1/2, β-actin, and α-tubulin were significantly reduced. Treatment with L-NAME led to an increase in the expression of the metalloprotease MMP-9. SK-MEL-28 cells in suspension and treated with the NOX4 inhibitor, GKT36901, exhibited reduced viability. This was accompanied by the inhibition of FAK phosphorylation at Tyr397, ERK 1/2 phosphorylation, and a reduction in the expression of FAK, ERK 1/2, β-actin, and α-tubulin, with a slight elevation in the expression of MMP-9. Migration and invasion were strongly inhibited in A375 cells upon treatment with L-NAME, while treatment with GKT36901 had a marginal effect on the migration and invasion capacities of SK-MEL-28 cells. In summary, melanoma cells employ nitrosative and oxidative stress to shield themselves from anoikis. Nitric oxide was essential for melanoma cells at the primary site for resisting anoikis, while H₂O₂ contributed to anoikis resistance in metastatic melanoma cells. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Although the lipid metabolism-associated gene PTGDS has been implicated in tumorigenesis, its functional significance and regulatory mechanisms in LUAD are poorly understood. Methods: We integrated multi-omics data from TCGA and GEO cohorts to evaluate PTGDS expression and its clinicopathological relevance. Functional characterization was performed using gain-of-function models in LUAD cell lines and a xenograft mouse model, assessing proliferation, migration, invasion, and immune microenvironment alterations. Results: PTGDS expression is markedly reduced in LUAD tissues and correlates strongly with advanced disease stage and unfavorable prognosis. Clinically, low PTGDS expression is associated with specific driver mutations and reduced tumor mutation burden. Notably, PTGDS levels correlate with enhanced cytotoxic T-cell infiltration and suppressed M2 macrophage polarization, suggesting immunomodulatory functions. Ectopic expression of PTGDS significantly suppressed malignant behaviors in vitro and tumor growth in vivo. Mechanistically, PTGDS overexpression was associated with reduced expression of CDK1 and PLK1 and increased expression of p21 and p27. Conclusions: Our findings establish PTGDS as a novel tumor suppressor in LUAD that restrains tumor progression through cell cycle modulation and immune microenvironment remodeling, highlighting its potential as both a prognostic biomarker and a therapeutic target. Full article

Background: Esophageal squamous cell carcinoma (ESCA) represents one of the most common aggressive malignancies worldwide. Insulin-like growth factor binding protein 1 (IGFBP1), a typical member of the IGF superfamily, is closely linked to adverse prognosis in numerous cancers. Up to now, little is known about its functional relevance to cell migration and tumor progression in ESCA. This work focuses on clarifying the relationship between IGFBP1 expression and the progression and migratory characteristics of ESCA. Methods: mRNA expression profiles from ESCA patients were obtained from the TCGA and GEO databases. Differential expression analysis was performed using R software(version 4.2.2), followed by an intersection of DEGs between datasets. The STRING database was applied to establish PPI networks. Cytoscape software(Version 3.7.2) was then used for visual presentation and hub gene identification. IGFBP1 expression was validated in ESCA tissues versus adjacent normal tissues. Prognostic correlation was assessed using GEPIA, while diagnostic and predictive values were evaluated through ROC analysis and Cox regression. Genetic alterations of IGFBP1 were analyzed via cBioPortal. Immune cell infiltration patterns were investigated using TIMER. Functional enrichment analyses (GO, KEGG) were performed on IGFBP1-associated DEGs. In the in vitro experiments, esophageal cancer cell lines (such as Eca109 and TE-1) and normal human esophageal epithelial cell lines (such as HEEC) were selected. The transcriptional level of IGFBP1 was examined using RT-qPCR, while Western blot analysis was conducted to validate its protein expression changes. Changes in the proliferative capacity of cancer cells after IGFBP1 silencing were detected by the CCK-8 assay, and cell migration capacity was determined via wound scratch assays to clarify the related biological effects. Results: Overall, 2870 DEGs were screened from the GEO database, 153 DEGs were screened from the TCGA database, and 34 genes were found to be common to both databases; 10 core genes were screened from the PPI network. IGFBP1 was abnormally expressed in esophageal cancer. Cox regression confirmed that IGFBP1 is an independent risk factor, and prognostic analysis indicated that IGFBP1 is closely associated with poor prognosis. Gene mutation analysis showed that amplification mutations are the most common type of IGFBP1 gene mutation, and genetic alterations in IGFBP1 in ESCA patients are significantly associated with overall survival (OS) (p = 0.0002568). GO analysis indicated that IGFBP1-related differentially expressed genes were enriched in organic anion transport, epidermal development, apical cell components, and metal ion transmembrane transporter activity. Pathway enrichment based on the KEGG database illustrated the main enrichment of target genes in neuroactive ligand–receptor interactions, calcium signaling and cAMP signaling pathways. Additionally, remarkable differences in immune cell infiltration were observed between IGFBP1 high-expression and low-expression subgroups through tumor immune profiling. IGFBP1 expression differed significantly between esophageal cancer cells and normal esophageal epithelial cells, as detected by RT-qPCR (p < 0.05). Moreover, knockdown of IGFBP1 markedly inhibited the proliferation (p < 0.05) and migration abilities (p < 0.05) of TE-1 and Eca109 cells. Conversely, IGFBP1 overexpression facilitated these cellular processes. Conclusions: As a key oncogenic driver for ESCA, IGFBP1 may participate in the oncogenesis of ESCA, possibly influencing clinical outcomes via IGF signaling and the tumor microenvironment. Its dual functions in tumor and immune systems suggest it might be a candidate for ESCA immunotherapy research. Full article

Drug repurposing presents as a promising strategy in oncology, particularly for urological prostate and bladder cancers, where resistance to current therapy remains a challenge. This study evaluated the anticancer potential of three antiretroviral drugs, namely ritonavir (RIT), saquinavir (SAQ), and rilpivirine (RPV), in PC-3 and UM-UC-5 cancer cell lines, using MTT, clonogenic, wound healing, toxicity assessment with fibroblast cells, and DCFDA assays; this last method included efavirenz (EFV) and etravirine (ETV) for intracellular reactive oxygen species (ROS) production. RIT and SAQ showed stronger antiproliferative effects than RPV, with lower concentration- and cell-line-dependent activity, while clonogenic assays confirmed a reduction in long-term proliferation, particularly for RIT in both cell lines and SAQ for UM-UC-5. In contrast, effects on cell migration were limited for all drugs. ROS production was cell-dependent, with EFV increasing ROS in PC-3 and SAQ and RIT in UM-UC-5 cells. Generally, all drugs showed minimal toxicity in non-malignant cells, with SAQ exhibiting some toxicity but only for concentrations higher than those required for anticancer activity. Overall, these findings suggest that antiretroviral, especially protease inhibitors, may cause anticancer effects, although these are concentration- and context-dependent, and further investigation is needed to understand the mechanisms involved. Full article

Recent studies indicate that ferroptosis shows unique advantages in oncotherapy, particularly in reversing multidrug resistance (MDR). Despite current therapeutic advancements, the treatment of high-incidence malignancies with dismal prognoses continues to face challenges, including limited clinical efficacy, significant side effects, and drug resistance. In recent years, Chinese herbal medicine (CHM) has gained increasing attention in anti-tumor therapy. CHM bioactive components are highly effective in inducing tumor cell ferroptosis, inhibiting tumor proliferation and migration, and reversing drug resistance. Additionally, some components can protect normal cells and improve the tumor microenvironment. This review systematically summarizes the regulatory roles of various CHM bioactive components in ferroptosis across common human cancers. We further analyze the underlying molecular mechanisms, focusing on the modulation of key regulatory targets (e.g., GPX4, SLC7A11, and Nrf2) and critical signaling cascades (e.g., PI3K/AKT/mTOR and p53). Furthermore, the differential effects of bioactive compounds from CHM on common tumors were evaluated, alongside their potential in combination therapy. This review provides a theoretical foundation for the development of novel anticancer drugs targeting ferroptosis regulation and offers new perspectives for the clinical application of CHM in oncology. Full article

The p53 protein is a pivotal tumor suppressor that is mutated in more than half of tumor cases in humans. In addition, its activity/function can be perturbed by various other mechanisms. Existence of two promoters in the TP53 gene and extensive splicing on N- and C-terminus, as well as alternative translation initiation, give rise to numerous p53 protein isoforms. Different p53 protein isoforms can form heterotetramers with canonical full-length p53 or compete in binding target genes’ promoters as tetramers which can result in modulation of p53 function. In this review we have gathered the most novel research on the p53 isoform network including the isoforms’ expression profiles and biological functions in the most frequent cancer types. The expression of p53 isoforms differs among tumor types and compared with normal tissues, thereby affecting biological processes associated with tumorigenesis, such as apoptosis, cell cycle regulation, migration, senescence, stemness, etc. We also discussed the potential of targeting p53 isoforms by direct mechanisms that can change the ratio between specific isoforms and thus modulate their activity or indirectly by targeting downstream pathways regulated by a specific isoform. More profound understanding of the p53 pathway regulation could contribute to improvement in current therapies. Full article

Mechanisms of primary and acquired resistance are responsible for treatment failure with the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) in the majority of patients with advanced Non-Small-Cell Lung Cancer (NSCLC) carrying EGFR-activating mutations. MicroRNAs (miRNAs) are important modulators of EGFR signaling in lung cancer. Recent studies suggested the role of miR-23c as a tumor suppressor or oncogenic miRNA in different tumor types. However, the role of miR-23c in NSCLC carrying EGFR mutations and its involvement in resistance to EGFR-TKIs has not been explored yet. We found that miR-23c was strongly downregulated in H1975 and HCC827-Gefitinib-Resistant (GR) NSCLC cell lines with intrinsic and acquired resistance to gefitinib, respectively, as compared to gefitinib-sensitive cell lines. Moreover, we demonstrated that miR-23c mimic inhibited proliferation, migration, invasion, and epithelial–mesenchymal transition of resistant cells and that Interleukin-6 Receptor (IL-6R) is a direct target of miR-23c in H1975 and HCC827-GR cell lines. Importantly, miR-23c mimic re-sensitized NSCLC-resistant cells to gefitinib, whereas the combination of miR-23c mimic with a neutralizing IL-6R antibody potentiated the sensitivity to the drug. Collectively, our data demonstrated that miR-23c acts as a tumor suppressor in NSCLC cell lines carrying EGFR mutations and that the axis miR-23c/IL-6R might represent a potential target for the development of therapeutic approaches to overcome resistance to gefitinib. Full article

Background: Epithelial ovarian cancer (EOC) is characterized by aggressive peritoneal dissemination and an immunosuppressive tumor microenvironment in which tumor-associated macrophages (TAMs) play a central role. Chemokine signaling pathways regulate macrophage recruitment and function; however, the contribution of the CX3CL1–CX3CR1 axis to ovarian cancer progression and TAM-mediated effector mechanisms remains unclarified. This study aimed to clarify the role of CX3CL1–CX3CR1 signaling in ovarian cancer progression, focusing on macrophage-derived pro-tumorigenic factors. Methods: CX3CL1 and CX3CR1 expression was examined in human EOC and healthy ovarian tissues by real-time polymerase chain reaction and immunohistochemistry. Functional effects of CX3CL1 on ovarian cancer cells were evaluated via migration and proliferation assays in the murine ID8 cell line. An intraperitoneal syngeneic ovarian cancer model was established by injecting ID8 cells into wild-type and Cx3cr1-deficient mice. Tumor burden, ascites formation, survival, macrophage infiltration, and expression levels of matrix metalloprotease-2 (MMP-2) and transforming growth factor-β (TGF-β) were assessed by histological, immunohistochemical, and molecular analyses. Results: CX3CL1 and CX3CR1 expression was significantly upregulated in human EOC tissues and associated with marked macrophage infiltration. CX3CL1 stimulation enhanced migration, but not proliferation, of ID8 cells. Cx3cr1 deficiency significantly suppressed intraperitoneal tumor growth, reduced ascitic fluid volume, and prolonged survival. This was accompanied by reduced CX3CR1⁺ TAM accumulation and decreased MMP-2 and TGF-β expression, which were predominantly produced by infiltrating macrophages. Conclusions: The CX3CL1–CX3CR1 axis promotes ovarian cancer progression by recruiting MMP-2- and TGF-β-producing macrophages. Targeting CX3CR1-dependent TAM functions may represent a therapeutic strategy for limiting peritoneal dissemination in ovarian cancer. Full article

The mechanosensitive PIEZO family channels, PIEZO1 and PIEZO2, are essential for mechanotransduction and play roles in many cellular processes, including cell volume regulation, tissue development, touch sensation, and proprioception. Emerging evidence suggests roles for PIEZO channels in cancer biology; however, direct mechanistic evidence in breast cancer remains limited. They have been shown to promote proliferation, epithelial-to-mesenchymal transition (EMT), and migration; however, these roles are varied and context-dependent. In breast cancer specifically, the two PIEZO channels may play opposing and complex roles in tumor progression, the tumor microenvironment (TME), and the tumor immune microenvironment (TIME), potentially impacting therapeutic response and prognosis. Where breast cancer-specific mechanistic data are lacking, we integrate findings from other tumor types to generate testable hypotheses relevant to breast cancer. In this review, we will explore the importance of PIEZO channels in breast cancer development, progression, and therapeutic response, and explore therapeutics and potential strategies to improve patient outcomes. Full article