Search Results (2,437)

This study aimed to elucidate the oncogenic role of FOXA1(forkhead box A1) in ovarian cancer and to evaluate its potential as both a therapeutic target and a diagnostic biomarker. We further investigated whether FOXA1 inhibition could enhance responsiveness to immune checkpoint blockade and overcome chemoresistance. A total of seventy-six ovarian tissue samples were analyzed, including nine normal, thirty-four benign, and thirty-three malignant specimens. IHC (immunohistochemistry) staining was performed to assess FOXA1 expression and its correlation with tumor stage. Functional studies were conducted using FOXA1 siRNA in SK-OV3 and HEYA8 cell lines. Changes in cell proliferation, migration, invasion, and wound-healing ability were evaluated following FOXA1 silencing. Quantitative RT-PCR was used to measure the expression of FOXA1 and EMT (epithelial–mesenchymal transition)-related genes. The effects of FOXA1 inhibition on sensitivity to carboplatin and the immune checkpoint inhibitor atezolizumab were also examined. IHC analysis revealed significant differences in FOXA1 expression among normal, benign, and malignant tissues, with levels correlating with tumor stage. FOXA1 silencing significantly reduced proliferation and decreased migration and invasion by 60–80%, accompanied by marked downregulation of EMT-related genes. Moreover, FOXA1 inhibition enhanced atezolizumab responsiveness and reduced carboplatin resistance in ovarian cancer cells. In summary, FOXA1 acts as an oncogenic driver in ovarian cancer, promoting proliferation, invasion, and EMT activation. Its overexpression correlates with disease progression, supporting its potential as a biomarker and therapeutic target. Targeting FOXA1 could enhance immunotherapy efficacy and help overcome chemoresistance in ovarian cancer. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related deaths in advanced disease, and activating KRAS/NRAS mutations limit the use of anti-EGFR antibodies to RAS–wild-type tumors. The cellular prion protein (PrP^C) has been linked to aggressive and chemoresistant CRC, but its extracellular partners and functional relevance in KRAS-mutant disease are not fully defined. Here, we examined extracellular PrP^C complexes and PrP^C-associated signaling in CRC cell lines and xenografts using a neutralizing PrP^C monoclonal antibody. Across a CRC panel that included SNU-C5/WT and its 5-fluorouracil- and oxaliplatin-resistant derivatives, HT-29 (KRAS–wild-type), and HCT-8 and LoVo (KRAS-mutant), co-immunoprecipitation showed that PrP^C forms complexes with the 37/67 kDa laminin receptor (RPSA), with PrP^C–RPSA association particularly increased in KRAS-mutant HCT-8 and LoVo cells. PrP^C protein levels were higher in KRAS-mutant HCT-8, SW620, and SNU-407 cells than in HT-29, and PrP^C neutralization reduced viability in all four lines. Accordingly, we assessed upstream RAS activity and found that active RAS (RAS-GTP) was higher in KRAS-mutant cells than in HT-29, and PrP^C treatment was associated with reduced RAS-GTP levels. In the same KRAS-mutant setting, basal AKT phosphorylation exceeded that in HT-29, and PrP^C treatment lowered AKT phosphorylation without changing total AKT. Moreover, PrP^C treatment was associated with reduced ERK1/2 phosphorylation in KRAS-mutant cells, suggesting attenuation of downstream RAS pathway output. These signaling changes coincided with a decrease in the S-phase fraction and an increase in G1. In an HCT-8 (KRAS G13D) xenograft model, PrP^C monotherapy inhibited tumor growth in a dose-dependent manner, and 5-fluorouracil (5-FU) monotherapy produced an intermediate effect. The combination of PrP^C (10 mg/kg) and 5-FU (20 mg/kg) yielded the greatest tumor growth inhibition among the tested regimens. Consistent with this enhanced tumor control, immunofluorescence of xenograft tissues showed that PrP^C, particularly with 5-FU, reduced intratumoral PrP^C and PCNA and decreased CD31-positive microvessels and α-SMA–positive vessel structures. Taken together, these findings suggest that extracellular PrP^C supports RAS–AKT signaling, proliferation, and tumor-associated angiogenesis in KRAS-mutant colorectal cancer, and that PrP^C neutralization additively enhances 5-fluorouracil activity in KRAS-mutant models. The data provide a preclinical basis for evaluating PrP^C antibodies in combination with fluoropyrimidine-based regimens in patients with KRAS-mutant CRC. Full article

Ovarian cancer remains the most lethal gynaecological malignancy primarily due to late-stage diagnosis, high recurrence rate, and limited treatment efficacy. Current diagnostic tools, including imaging and serum markers, lack sufficient sensitivity and specificity for early detection. Increasing evidence highlights the critical role of myeloid-derived immune cells within the tumour microenvironment in shaping ovarian cancer progression and therapy response. Monocytes and their derivatives are central regulators of immune suppression, chemoresistance, and metastatic dissemination in ovarian tumours. Their recruitment and polarisation are governed by several signalling pathways offering promising therapeutic targets. Strategies including monocyte depletion, TAM reprogramming, MDSC maturation, DC vaccines, and their synergistic use with chemotherapy or immune checkpoint inhibitors are being explored to restore anti-tumour immunity in ovarian cancer. Parallel to therapeutic potential, the lymphocyte-to-monocyte ratio and its reciprocal monocyte-to-lymphocyte ratio have also emerged as potential accessible and cost-effective prognostic tools that predict disease aggressiveness and survival in ovarian cancer. This review features the diagnostic, prognostic, and therapeutic significance of monocytes and their derivatives in ovarian cancer management and highlighting new opportunities for next-generation immunomodulatory therapies. Full article

Epithelial ovarian cancer (EOC) represents the most lethal malignancy arising from the female reproductive tract, largely due to the clinical challenge of chemotherapy resistance. Recent studies indicate that ferroptosis—a distinct form of programmed cell death driven by iron accumulation and lipid peroxidation, could potentially exploit a vulnerability in chemoresistant cancer cells. Here, we identify MED12 as a critical regulator of ferroptosis sensitivity in EOC through modulation of the YAP–TEAD1 signaling pathway. Using CRISPR/Cas9-mediated knockout and rescue experiments in EOC cell lines, we demonstrate that MED12 deficiency significantly enhances sensitivity to ferroptosis inducers (RSL3 and Erastin), as evidenced by reduced IC50 values. Transcriptomic and chromatin accessibility analyses reveal that MED12 loss activates YAP signaling through TEAD1 upregulation, increasing chromatin accessibility at YAP–TEAD1 target loci and elevating the expression of downstream effectors CYR61 and CTGF. Pharmacological inhibition of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferroptosis sensitivity in MED12-deficient cells, confirming pathway specificity. These findings establish MED12 as a modulator of the YAP–TEAD1–ferroptosis axis and suggest that targeting this pathway could overcome chemoresistance in MED12-deficient EOC. Our work provides a mechanistic foundation for exploiting ferroptosis induction as a therapeutic strategy in ovarian cancer. Full article

Despite a thorough understanding of the structure of human papillomavirus (HPV) and its genotypic variations (high-risk and low-risk variants), the mechanisms underlying HPV-induced cervical cancer (CC) pathogenesis and the molecular signatures of drug resistance remain to be fully understood. Accumulating evidence has shown the involvement of kinase targets in the induction of drug resistance in high-risk (HR) HPV-CC. Molecularly, the genome of high-risk HPV is reported to control the expression of host kinases. In particular, Aurora kinases A, B, and C (ARKA, ARKB, and ARKC), phosphotidylinositol–trisphosphate kinase (PI3K)-Akt, and Glycogen synthase kinase3-α/β (GSK3 α/β) promote the transformation of infected cells, and also enhance the resistance of cells to various chemotherapeutic agents such as nelfinavir and cisplatin. However, the precise mechanisms through which HPV activates these kinases are yet to be fully elucidated. Furthermore, there is still ambiguity surrounding whether targeting HPV-induced kinases along with HPV-targeted therapies (such as phytopharmaceuticals and PROTAC/CRISPR-CAS-based systems) synergistically inhibit cervical tumor growth. Given the critical role of kinases in the pathogenesis and treatment of CC, a comprehensive review of current evidence is warranted. This review aims to provide key insights into the mechanisms of HPV-induced CC development, the involvement of kinases in drug resistance induction, and the rationale for combination therapies to improve clinical outcomes. Full article

Background/Objectives: Epithelial ovarian cancer (EOC) is often diagnosed at advanced stages, with metastasis driven by spheroid dissemination within the peritoneal cavity. We previously demonstrated that autophagy supports spheroid cell survival and suggest that it contributes to chemoresistance. Unc-51-like autophagy activating kinase 1 (ULK1), a key regulator of autophagy, has emerged as a promising therapeutic target. Here, we evaluated the effects of ULK1 inhibition via MRT68921, alone and in combination with afatinib—a tyrosine kinase inhibitor (TKI) known to induce pro-survival autophagy—in EOC. Methods: High-grade serous (HGSOC) and ovarian clear cell carcinoma (OCCC) cell lines were cultured under adherent and spheroid conditions. Immunoblotting confirmed on-target effects and modulation of autophagy. Autophagic flux was assessed using mCherry-eGFP-LC3 reporter assays. We assessed 96 dose combinations of MRT68921 and afatinib using drug combination matrices, with synergy evaluated via Synergy Finder. Promising combinations were evaluated across multiple EOC spheroid models and patient ascites-derived organoids. Results: MRT68921 inhibited ULK1 activity and reduced autophagic flux in a context-dependent manner while afatinib alone induced autophagy. Their combination produced synergistic effects at select concentrations, impairing spheroid reattachment and viability. However, MRT68921 alone significantly reduced viability across multiple EOC models, including patient ascites-derived organoids. Conclusions: This study is the first to evaluate the combined effects of MRT68921 and afatinib in epithelial ovarian cancer. Our findings demonstrate that ULK1 inhibition via MRT68921 consistently reduces cell viability across multiple ovarian cancer models, supporting ULK1 as a promising therapeutic target. In contrast, combination with afatinib produced limited and context-dependent effects, indicating that further investigation is needed to identify optimal combination strategies for ULK1-targeted therapies. Full article

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial–mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH⁺ and CD44⁺/CD24⁻ fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit. Full article

Ovarian cancer remains a top mortality contributor within gynecological cancers because patients receive diagnoses late in the disease course and conventional treatment resistance along with high recurrence rates cause poor outcomes. Aberrant regulation of autophagy and apoptosis has a critical role in the development, progression, chemoresistance, and immune escape from ovarian cancer. Recent evidence has demonstrated a complicated and dynamic crosstalk between autophagy and apoptosis, during which autophagy can act as a cytoprotective or cell death-promoting process depending on tumor stage and therapeutic context. In parallel, apoptosis functions as a tightly regulated form of programmed cell death that is essential for eliminating damaged or malignant cells and serves as a major tumor-suppressive mechanism in ovarian cancer. The PI3K/AKT/mTOR signaling pathway is the most active and clinically relevant pathway in the management of ovarian cancer as a master regulator of both autophagy and apoptosis, suppressing apoptotic cell death while promoting cytoprotective autophagy under chemotherapeutic stress. Bioactive natural products derived from plants, marine sources, and dietary intake have emerged as potential modulators of the autophagy-apoptosis crosstalk. Curcumin, resveratrol, quercetin, berberine, and epigallocatechin gallate are known to have the ability to restore apoptotic signaling, block pro-survival autophagy, and sensitize ovarian cancer cells to chemotherapy through the regulation of key pathways including PI3K/AKT/mTOR, AMPK, MAPK, p53, and Bcl-2 family proteins. In this review, we provide an updated understanding of the molecular mechanisms through which bioactive natural products modulate autophagy–apoptosis crosstalk in ovarian cancer. We also highlight the translational challenges, therapeutic potential, and future directions for the integration of natural product-based strategies in precision medicine for ovarian cancer. Full article

Ovarian cancer is one of the deadliest gynecological malignancies, where most patients become clinically symptomatic at advanced stages of disease due to the lack of effective diagnostic screening. Despite recent advances in surgical resection and chemotherapy, recurrent ovarian cancer remains largely refractory to treatment, resulting in poor prognosis. The ovarian cancer tumor microenvironment (TME) is highly abnormal and presents a significant barrier to successful therapy. A combination of abnormal vasculature, desmoplastic extracellular matrix, and aberrantly activated hypoxic and immune-suppressive pathways culminates in promoting tumor growth, dissemination, chemoresistance, and immunosuppression. Whilst immune checkpoint inhibitors have shown success in other cancers, their application in ovarian cancer, particularly at advanced stages, remains limited. In this review, we discussed the application of tumor extracellular matrix normalizing therapies in preclinical models of advanced ovarian cancer, and their synergistic benefit to chemotherapy and immunotherapy. Collectively, these insights underscore TME normalization as a promising therapeutic strategy with the potential to improve ovarian cancer management. Full article

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article

Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53-mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology of TP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody–drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-κB, CCRL2, and HIF-1α), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53-mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need. Full article

Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), remains a highly lethal disease because of its late diagnosis, significant biological heterogeneity, and frequent resistance to therapy. Growing evidence indicates that microRNAs (miRNAs) are key posttranscriptional regulators involved in tumor initiation, progression, metastasis, and response to treatment. This review provides a comprehensive and updated overview of miRNA dysregulation in both ESCC and EAC, with a specific focus on its emerging clinical relevance in early detection, prognostic assessment, and prediction of therapeutic response. Multiple tissue-based and circulating miRNA signatures, some capable of distinguishing between Barrett’s esophagus (BE), dysplasia, and EAC, demonstrate promising diagnostic performance. In parallel, several miRNAs, including miR-21, miR-23a, miR-455-3p, and miR-196b, have been consistently associated with chemoresistance and radioresistance. Moreover, distinct miRNA expression patterns are correlated with tumor aggressiveness, metastatic potential, and the risk of recurrence, supporting their integration with conventional histopathological and molecular parameters for improved patient stratification. Overall, miRNAs represent a powerful class of biomarkers and potential therapeutic targets in EC, with increasing translational relevance in precision oncology. Full article

Ovarian cancer (OC) remains the leading cause of death among gynecologic cancers. Most women diagnosed with OC at advanced stages eventually develop relapse and chemoresistance, leading to poor clinical outcomes. While piRNAs have emerged as critical regulators of gene expression and tumor biology, their specific roles in OC remain to be fully elucidated. This study integrated clinical and computational analyses to investigate the expression pattern and functional relevance of P-element-induced wimpy testis (PIWI)-interacting RNA-823 (piR-823) and its associated protein piwi-like RNA-mediated gene silencing 1 (PIWIL1)/DNA methyltransferase 3B (DNMT3B)/E-cadherin (CDH1) axis in OC tissues from 40 patients, with 20 non-cancer control samples. Expression profiling was performed using qPCR on OC and normal ovarian tissues, followed by correlation and regression analyses. Public databases, including GEPIA, TNM plot, and MethBank, were explored to validate gene expression, methylation status, and pathway enrichment. Our results revealed that piR-823, PIWIL1, and DNMT3B were significantly upregulated in OC tissues (p < 0.001, p = 0.009, and p < 0.001, respectively), and they correlated positively with each other and inversely with CDH1 expression. CDH2, OCT4, and NANOG were significantly upregulated (p = 0.011, p = 0.03, and p < 0.001, respectively), whereas CDH1 expression was significantly downregulated (p < 0.001) in OC tissues. In silico analyses supported DNMT3B-mediated CDH1 promoter methylation, epithelial–mesenchymal transition (EMT), and stemness pathway enrichment. Our integrated computational and clinical analyses indicate that the piR-823/PIWIL1/DNMT3B/CDH1 axis is a putative epigenetic regulator of EMT and cancer stemness in ovarian cancer. Additionally, piR-823 may serve as a promising prognostic biomarker and therapeutic target, offering novel insights into OC pathogenesis and treatment. Full article

This study investigates the impact of microresistor topology on the sensing characteristics of MoS₂-based chemoresistive cortisol sensors. It is done to address the critical need for robust, non-invasive cortisol monitoring in wearable applications, where mechanical stability under strain is paramount, and to explore underexplored topological effects on sensor performance. The research is conducted by fabricating MoS₂-based meander structures on flexible PDMS substrates, featuring various microresistor designs, including long-shoulder and short-shoulder topologies, both with and without integrated mechanical ribs. Sensor performance is evaluated in resistance change mode across a range of cortisol concentrations (2.5 to 500 ng/mL) and subjected to significant mechanical bending stress. Electrical parameters such as contact resistance and parasitic capacitance, as well as temperature dependence, are also analyzed. The results demonstrate that the incorporation of ribs significantly enhances the mechanical stability and preserves the reliable sensing function of the long-shoulder topology under bending stress, improving sensitivity from 0.9 kΩ/ng/mL (without ribs) to 130.6 kΩ/ng/mL (with ribs) after bending. While temperature influences baseline resistance and response magnitude consistent with MoS₂ semiconductor properties and aptamer binding kinetics, the short-shoulder design, even with ribs, showed less optimal performance. The primary advantage of the proposed device lies in its enhanced mechanical reliability under continuous strain, crucial for wearable electronics, alongside a simpler design compared to complex microfluidic or optical systems, thus enabling lower manufacturing costs and easier mass production. Full article

Gastric cancer (GC) is the fifth most common type of cancer and a leading cause of cancer-related deaths worldwide. Surgery remains the most effective treatment, but new therapeutic strategies are urgently needed. The use of natural polyphenolic compounds such as curcumin (CUR) and resveratrol (RSV) has played a significant role in this effort. This review provides a comprehensive overview of the current applications and molecular mechanisms of curcumin and resveratrol in gastric cancer, highlighting their therapeutic potential and translational relevance. Analytically, CUR induces apoptosis, endoplasmic stress and cell cycle arrest. On the other hand, resveratrol enhances apoptosis and reduces inflammation. Both compounds increase cancer cell sensitivity to chemotherapy and help prevent chemoresistance, highlighting their potential as molecular enhancers in anticancer therapy. Combined with standard therapeutic drugs, they represent an innovative strategy for GC treatment. By presenting these innovative approaches, this review offers a global perspective on how their administration could shape future treatment strategies. Full article