Search Results (987)

Background/Objective: This study aimed to use multiple disk domain receptor 1 (DDR1), transforming growth factor β1 (TGFβ-1), tumor-associated calcium signal transduction protein 2 (TACSTD2), and polyligand proteoglycan 1 (SDC1) siRNA to treat pancreatic cancer with the goals of high specificity, significant therapeutic efficacy, and relatively low toxicity. Methods: (1) A microfluidic method was used to prepare siRNA-LNPs with different formulations. (2) Quantitative PCR (qPCR) and Western blot assays were used to detect the inhibitory effect of different-prescription siRNA-LNP formulations on mRNA and protein expression levels of related genes in PaTu 8988 pancreatic cells. (3) The anti-pancreatic cancer effect of multiple siRNAs combined with LNPs in vivo was evaluated using the BALB/c nude mouse model with subcutaneous pancreatic cancer xenografts. Results: (1) Three siRNA-LNP formulations, DMG, CE 1.5, and CE 0.75, were successfully prepared, exhibiting small particle sizes and uniform distribution. (2) qPCR and Western blot results indicated that DDR1, TGFβ-1, TACSTD2, and SDC1 siRNA-LNP significantly inhibited related genes’ mRNA and protein expression in pancreatic cancer PaTu 8988 cells. (3) Efficacy studies in animals indicated that multiple siRNA combined with LNPs in each group exhibited significant antitumor effects on pancreatic cancer tumor-bearing nude mice. The therapeutic efficacy of the combined siRNAs was superior to that of single siRNA treatments, indicating a clear combined effect, especially with three- and four-siRNA combinations. Conclusions: The prepared DDR1/TGFβ-1/TACSTD2/SDC1 siRNA-loaded LNP demonstrated a small particle size, high gene inhibition efficiency, and a significant therapeutic effect in treating pancreatic cancer. Its safety is generally acceptable, but attention should be paid to the toxicity caused by LNP excipients, especially cationic lipids. Full article

Prostate cancer (PCa) is among the highest incidence malignancies in men, with high rates of inevitable resistance development, relapse, and mortality. Castration-resistant prostate cancer (CRPC) continued to pose substantial therapeutic challenges, highlighting the urgent need for effective treatment options. This study assessed the marine cembranoid sarcophine activity against the progression and recurrence of the metastatic CRPC (mCRPC) in mouse xenograft models. Protein and phosphorylation levels were assessed by immunoblotting and mRNA expression by qPCR and RNA sequencing. The in vivo efficacy was evaluated through tumor progression over 3 weeks followed by primary tumor excision and recurrence monitoring over an 8-week course. Sarcophine significantly reduced the mCRPC CWR-R1ca tumor volume by 74.1% and suppressed the epigenetic regulators EZH2 and SMYD2; lineage plasticity factors ASCL1 and BRN2; Wnt/stemness signaling markers β-catenin and LGR6; AKT total expression and activation; and invasion-associated proteins TRPC4 and MMP2 in primary tumors. Sarcophine effectively prevented the mCRPC locoregional recurrence, as well as lung and spleen distant recurrences, and effectively reduced recurrence in other organs. Transcriptomics-RNA-Seq analysis of primary tumors identified 2697 downregulated and 3534 upregulated genes, indicating broad transcriptional reprogramming following sarcophine treatments. These findings demonstrate coordinated suppression of multi-oncogenic pathways and validate the therapeutic potential of sarcophine to control mCRPC. Full article

Background: Acquired tolerance to temozolomide (TMZ) remains one of the main obstacles to enduring therapeutic success in glioblastoma (GBM). While tumor-derived extracellular vesicles are known to orchestrate therapy evasion by horizontally transferring molecules across the tumor microenvironment, the precise regulatory roles of specific exosomal circular RNAs (circRNAs) in establishing this refractory state require further elucidation. Methods: The expression of circ_0050688 in TMZ-resistant GBM clinical tissues and cell lines was evaluated. Exosomes derived from resistant cells were isolated and confirmed via transmission electron microscopy (TEM) and marker analysis. PKH67 fluorescent tracking was utilized to visually demonstrate exosome internalization by sensitive recipient cells. Biological functions, including the expression of the multidrug resistance protein P-glycoprotein (P-gp) and the proliferation marker Ki-67, were evaluated. The competing endogenous RNA mechanism was validated using RNA FISH, dual-luciferase reporters, and functional rescue experiments. In vivo efficacy was determined using subcutaneous xenograft mouse models. Results: Clinical and in vitro analyses revealed that circ_0050688 is upregulated in TMZ-refractory GBM, predicting adverse patient survival. Through PKH67-based tracing, we confirmed that resistant cells actively secrete circ_0050688-enriched exosomes, which are subsequently engulfed by drug-sensitive bystander cells. This vesicular transfer directly instigates a chemoresistant and highly proliferative phenotype, marked by elevated P-gp and Ki-67 levels. At the molecular level, circ_0050688 operates as a molecular decoy for miR-508-5p, thereby preventing the suppression of its downstream target, MDM2. Functionally, circ_0050688 depletion eradicated these aggressive traits and restored TMZ vulnerability across both cellular and murine xenograft models. Furthermore, rescue assays confirmed that this circ_0050688-driven chemoresistance is fundamentally dependent on the miR-508-5p/MDM2 signaling axis. Conclusions: Current data uncover an intercellular signaling network driven by vesicular circ_0050688, which functions as a mobile oncogene to reshape the TMZ-refractory microenvironment. Targeting this exosomal circ_0050688/miR-508-5p/MDM2 network to suppress P-gp and Ki-67 expression represents a highly promising therapeutic strategy for refractory GBM. Full article

We previously showed that TCEA1 deficiency in myeloid cells promotes proliferation, impairs differentiation and inhibits apoptosis, but its role and underlying mechanism in acute myeloid leukemia (AML) are unknown. Here, in NB-4 cells, an M3 subtype of AML, TCEA1 overexpression suppressed proliferation (p < 0.001), induced S-phase arrest (from 35.35% to 19.47%, p < 0.001), increased apoptosis (from 10.37% to 23.5%, p < 0.001), and promoted differentiation. Mechanistically, TCEA1 overexpression upregulated C/EBPε and IRF8 at the mRNA and protein levels; conversely, TCEA1 knockdown downregulated both. Rescue experiments in TCEA1 knockdown 32Dcl3 cells showed that ectopic C/EBPε or IRF8 reversed the uncontrolled proliferation, blocked apoptosis, and impaired differentiation. In xenograft mouse models, TCEA1 overexpression reduced leukemic infiltration in the bone marrow, spleen, and liver; extended overall survival; and elevated C/EBPε and IRF8 expression in vivo. Analysis of public APL datasets revealed that high TCEA1 expression is associated with a favorable prognosis (HR = 0.43, 95% CI: 0.2–0.93, logrank p = 0.028). Collectively, our findings demonstrate that TCEA1 suppresses proliferation, promotes apoptosis and differentiation, and attenuates disease progression by upregulating C/EBPε and IRF8, positioning this regulatory mechanism as a potential therapeutic target and prognostic biomarker for this disease. Full article

Gastric cancer remains a major clinical challenge, underscoring the need for more effective drug delivery strategies. Approximately 10–20% of gastric cancers overexpress HER2, conferring aggressive tumor characteristics and poor survival, yet resistance to trastuzumab-based targeted therapy and limited intratumoral antibody penetration continue to restrict clinical outcomes. This study evaluated HER2-targeted exosomes as a delivery platform. Exosomes were engineered to express the p51 peptide, a high-affinity HER2-binding ligand, and loaded with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a potent HSP90 inhibitor. The cellular uptake and antitumor efficacy of p51-Exo^17-DMAG were assessed in vitro using NCI-N87 and AGS cells and in vivo using a mouse xenograft model. p51-modified exosomes exhibited superior HER2 specific uptake. Treatment with p51-Exo^17-DMAG significantly increased apoptosis, as demonstrated by elevated PARP and caspase3 cleavage, and downregulated oncogenic signaling molecules, including p-AKT, CDK2, VEGF, and c-Myc. Furthermore, p51-Exo^17-DMAG increased the number of TUNEL-positive cells. In the NCI-N87 xenograft model, systemic administration of p51-Exo^17-DMAG significantly inhibited tumor growth without toxicity or histological damage to major organs. Tumor analysis confirmed increased apoptosis and reduced proliferation in vivo. These findings demonstrate that p51-engineered exosomes provide an efficient, selective, and safe platform for HER2-targeted delivery of 17-DMAG, offering a promising precision medicine strategy for HER2-positive gastric cancer. Full article

Background/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM. 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

Nasopharyngeal carcinoma-associated malignant epithelial models remain useful for exploring integrin-related therapeutic strategies. In this study, we evaluated the antitumor activity and potential mechanisms of rRGD3^mu, a recombinant peptide with a triple-RGD architecture. Using CNE2 cells as the primary experimental model, we evaluated cell viability, colony formation, migration, invasion, adhesion, apoptosis-related marker expression, and EMT-associated molecular changes. In vivo efficacy was assessed using a CNE2 cell-derived BALB/c nude mouse xenograft model. rRGD3^mu inhibited CNE2 cell viability, clonogenic growth, migration, invasion, and adhesion in a dose-dependent manner and suppressed xenograft tumor growth under the tested dosing schedule. Mechanistically, rRGD3^mu promoted mitochondria-associated apoptosis, as indicated by an increased Bax/Bcl-2 ratio and caspase-9/3 activation, and modulated the expression of EMT-associated markers, including E-cadherin, N-cadherin, vimentin, and MMP2. Bioinformatic analysis and experimental validation suggested that ITGB1-containing integrin complexes might serve as important mediators and putative cellular engagement sites of rRGD3^mu. rRGD3^mu treatment reduced ITGB1 protein abundance and attenuated FAK/AKT signaling. ITGB1 knockdown partially mimicked the effects of rRGD3^mu and reduced the additional cellular response to rRGD3^mu treatment, supporting the substantial contribution of ITGB1-associated signaling. These findings provide preliminary mechanistic evidence that rRGD3^mu suppresses malignant phenotypes in CNE2-based models, at least in part through modulation of ITGB1-associated FAK/AKT signaling. Full article

Background/Objectives: Non-small-cell lung carcinoma (NSCLC) accounts for approximately 85% of lung cancers and remains a leading cause of cancer-related mortality. Although cisplatin is a cornerstone chemotherapeutic agent, its clinical effectiveness is limited by drug resistance and systemic toxicity. Capsaicin (CAP), a bioactive phytochemical derived from chili peppers, has demonstrated anticancer activity in several tumor types and has been investigated as a potential adjunct to conventional chemotherapy. Methods: An experimental study was conducted using A549 NSCLC cells and a xenograft mouse model. Cells were treated with CAP (50–300 µM), cisplatin (1 µg/mL), or their combination. Cell proliferation and apoptosis were evaluated using sulforhodamine B (SRB) assay, immunocytochemistry, and Western blot analysis. In vivo, tumor growth inhibition, histopathological alterations, and immunohistochemical expression of Ki-67 and cleaved caspase-3 were assessed. Results: Low CAP concentrations (50–100 µM) slightly increased proliferation, whereas concentrations ≥ 150 µM significantly reduced cell viability and induced apoptosis. Cisplatin monotherapy markedly suppressed proliferation and activated apoptosis. Bliss independence analysis demonstrated concentration-dependent synergy between CAP and cisplatin, with maximal synergy scores reaching 28.1 at 100 µM CAP. Combination treatment at CAP concentrations ≥ 150 µM produced the strongest antiproliferative effect in vitro and the highest tumor growth inhibition in vivo (88%). CAP did not further enhance cisplatin-induced apoptosis but significantly reinforced proliferation suppression with reduced Ki-67 expression. Conclusions: CAP exhibits biphasic dose-dependent effects in NSCLC and enhances cisplatin antitumor efficacy predominantly through proliferation suppression, supporting its further evaluation as an adjunctive phytochemical in cisplatin-based NSCLC therapy. Full article

Background: Tumor–stroma interactions play a critical role in renal cell carcinoma (RCC) progression. Cancer-associated fibroblasts (CAFs) are considered key components of the tumor microenvironment; however, their origin remains controversial. This study aimed to determine whether bone marrow-derived mesenchymal stem cells (MSCs) contribute to CAF-like stromal changes and RCC progression. Methods: An orthotopic xenograft mouse model was established using luciferase- and GFP-labeled Caki-1 cells. MSCs labeled with PKH26 were administered intravenously. Tumor growth was evaluated using an in vivo imaging system and tumor volume measurements. Immunohistochemical analyses were performed to assess MSC localization and α-smooth muscle actin (α-SMA) expression. In vitro proliferation and migration assays were conducted using direct and indirect co-culture systems. Results: The intravenous administration of MSCs significantly increased tumor growth and bioluminescence intensity in an orthotopic model. The tumor volumes were significantly larger in the MSC-treated versus control group. An immunofluorescence analysis demonstrated partial co-localization of PKH26-labeled MSCs with α-SMA-positive fibroblast-like cells, suggesting acquisition of CAF-like features. Direct co-culture with MSCs significantly enhanced RCC cell proliferation and migration in vitro, whereas culturing in conditioned medium alone did not produce similar effects. Conclusions: Exogenously administered bone marrow-derived MSCs may be recruited into RCC tissues and acquire CAF-like features through interactions with tumor cells. These findings suggest that stromal–tumor cell interactions within the tumor microenvironment may contribute to RCC progression and represent a potential therapeutic target. Full article

Background: Adipocytes play a critical role in the breast cancer tumorigenic microenvironment. However, their effects and underlying mechanisms remain unclear. This study aims to investigate the role of adipocytes in luminal A breast cancer invasiveness at the cellular and molecular levels. Methods: Various adipocyte types were co-cultured with MCF7 breast cancer cells in direct and indirect manners. Invasiveness was assessed via proliferation, migration, and invasion, with alterations examined at morphological, cellular, and molecular levels. The role of adipocytes on MCF7 was further explored using an orthotopic breast cancer xenograft mouse model. Results: MCF7 co-cultured with adipocytes, especially brown adipocytes (BAC), showed increased invasiveness and tumorigenic potential. Morphologically, co-cultivation with BAC increased the proliferation, EMT, and stemness of MCF7. Mechanistically, co-culture of MCF7 with BAC exhibited disturbed expression of genes related to adipogenesis and mitochondrial dynamics; notably, IRX3 was the most prominently elevated one. Knockdown of IRX3 restored balanced mitochondrial function and reduced both the invasiveness of breast cancer cells in vitro and tumor growth in vivo. Conclusions: Brown adipocytes promote breast cancer invasiveness by upregulating adipogenesis-related IRX3, which acts via the mitochondrial functional regulation. Full article

Background/Objectives: Advanced renal cell carcinoma (aRCC) remains incurable, with no established optimal sequence of targeted therapies due to interpatient heterogeneity and acquired resistance. We developed a luciferase-enabled patient-derived orthotopic xenograft (PDOX) avatar platform to evaluate sequential targeted therapies in individualized aRCC models that recapitulate tumor architecture, proliferation, angiogenesis, metastasis, and PD-L1 expression. Methods: Tumor specimens from two renal cell carcinoma (RCC) patients were expanded subcutaneously in NOD/SCID mice, transduced with luciferase/red fluorescent protein (Luc/RFP), and orthotopically implanted into mouse kidneys (KiCa-Pt58: sarcomatoid RCC, pT3aN1M1, Fuhrman grade 4; KiCa-Pt118: clear cell RCC with sarcomatoid component, pT3aNxM0, Fuhrman grade 4, respectively). Tumor growth and metastasis were monitored weekly by bioluminescence imaging (BLI). Mice were randomized into vehicle control or four sequential treatment groups (Everolimus→Sunitinib [E→S], Sunitinib→Everolimus [S→E], Pazopanib→Sunitinib [P→S], Pazopanib→Everolimus [P→E]). Drugs were administered orally three times weekly until resistance (>200% BLI increase), with one switch. At necropsy, tumor burden, ex vivo BLI metastasis, weights, H&E histology, and immunohistochemistry (Ki67, CD44, CD31, PD-L1) were assessed. Results: Two independent experiments were performed. In dosing optimization, PDOX tumors recapitulated parental histology and proliferative indices, mirroring patient trajectories. KiCa-Pt58 (metastatic sarcomatoid RCC; deceased 1-month post-nephrectomy) showed aggressive features: rapid engraftment at low doses, early growth (week 2), and lung metastases in 78% of mice (sacrifice day 34), reflecting a fulminant course. KiCa-Pt118 (non-metastatic; patient recurrence-free >8 years post nephrectomy) exhibited indolent behavior: delayed engraftment requiring higher doses plus lymph node stromal (HK) support, slower growth (week 4), no metastases, and later sacrifice (day 78), consistent with remission. In sequential therapy evaluation, for KiCa-Pt58, P→E yielded greatest reductions in tumor weight (p < 0.01), lung metastases (p < 0.01), Ki67+ proliferation, CD31+ angiogenesis, and PD-L1 expression versus control; E→S and S→E were also effective. For KiCa-Pt118, S→E and P→E reduced tumor burden (p < 0.01) and Ki67⁺ proliferation; S→E lowered CD31 and PD-L1. Conclusions: This RCC PDOX platform faithfully preserves patient-specific biology—including metastatic propensity, engraftment efficiency, growth kinetics, and stromal dependency—while enabling real-time evaluation of sequential targeted therapies. Given the limited number of models tested, these findings provide proof-of-concept for individualized treatment exploration in advanced RCC and support future investigation of rational combinations with immune checkpoint blockade in humanized or immunocompetent systems. Full article

Cervical cancer constitutes a major global health burden with a high incidence rate. Despite its well-established role in genome stability and cell cycle regulation, its specific anti-tumor mechanism involving the induction of a senescence-like state remains unclear. To determine whether Mg²⁺ impedes cervical cancer progression through the induction of a senescence-like phenotype via the ATM/CHK2/p21 pathway, HeLa cells were used in this study. Cell proliferation, migration, and invasion were measured using CCK-8, EdU, wound-healing, and Transwell assays, while SA-β-gal staining and western blotting served to examine both senescence-related markers and pathway protein expression. A BALB/c nude mouse xenograft model was established to evaluate tumor growth and safety following intratumoral Mg²⁺ injection. The results showed that Mg²⁺ inhibited proliferation, migration, and invasion in a concentration-dependent manner. Treatment with 20 mM Mg²⁺ increased SA-β-gal positivity, decreased Lamin B1 expression, and activated the ATM/CHK2/p21 pathway; moreover, this upregulation of p21 was reversed by an ATM inhibitor. ELISA revealed that 10 mM Mg²⁺ enhanced IL-6 and TNF-α secretion, confirming effective induction of the senescence-associated secretory phenotype, while higher concentrations diminished this effect, which may be partly attributed to the reduction in cell viability. In vivo experiments showed that Mg²⁺ inhibited tumor growth without notable alterations in body weight, liver and kidney function, or serum magnesium levels. In summary, the localized high concentration of magnesium ions induces cells to enter a senescence-like state via the ATM/CHK2/p21 pathway, thereby selectively suppressing malignant cellular behaviors. Notably, its in vivo efficacy and safety profile in vivo are favorable. It is also worth noting that these findings should be interpreted within the context of a preclinical, high-dose local Mg²⁺ model. Full article

Glypican-1 (GPC1) has emerged as a critical mediator of malignant tumor progression. GPC1 plays essential roles in regulating various signaling pathways involved in tumor cell proliferation, invasiveness, and tumorigenesis. Overexpression of GPC1 in tumors mediates oncogenic transformation, epithelial-to-mesenchymal transition, metastatic dissemination, and therapeutic resistance. Accordingly, GPC1-targeted therapeutic strategies have been investigated in clinical and preclinical studies. However, clinical efficacy has been limited. We previously developed an anti-GPC1 monoclonal antibody (mAb), G₁Mab-28 (mouse IgG₁, κ), which exhibits high affinity and specificity for GPC1. In the present study, we generated recombinant isotype-converted G₁Mab-28, including G₁Mab-28-mG_2a (mouse IgG_2a) and G₁Mab-28-hG₁ (human IgG₁). Both mAbs recognized GPC1-expressing human tumor cell lines, including lung squamous cell carcinoma PC-10 and pancreatic ductal adenocarcinoma PK-45H, by flow cytometry. Moreover, both mAbs exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against those cell lines. In mouse xenograft models, treatment with the mAbs resulted in potent antitumor efficacy against PC-10 and PK-45H tumors. Collectively, these findings support the therapeutic potential of G₁Mab-28 for the treatment of GPC1-positive tumors. Full article

Background: Breast cancer remains a leading cause of cancer-related mortality in women, largely due to metastasis and treatment resistance. ELF3, an ETS transcription factor, has been linked to cancer progression; however, the mechanisms regulating its activity remain incompletely understood. Methods: ELF3 expression and its association with patient survival were analyzed using GEO datasets and the Kaplan–Meier Plotter platform. Functional studies were performed using ELF3 knockdown in breast cancer cell lines, followed by WST-1 assays and crystal violet staining. Protein–protein interactions were evaluated using co-expression analysis, immunofluorescence, split luciferase complementation, GST pull-down, and yeast two-hybrid assays. Cycloheximide chase assays were conducted to assess ELF3 protein stability. A panel of small molecules was screened to identify inhibitors of the ELF3-HSP27 interaction, and a lead compound was further validated using biochemical and functional assays. Antitumor activity was evaluated in a xenograft mouse model. Results: High ELF3 expression was associated with poorer overall survival in breast cancer patients. HSP27 was identified as a binding partner that stabilizes ELF3 protein, thereby promoting breast cancer cell proliferation. A novel small-molecule inhibitor disrupting the ELF3-HSP27 interaction suppressed cancer cell growth in vitro and reduced tumor growth in vivo. Conclusions: The ELF3-HSP27 interaction represents a previously unrecognized contributor to breast cancer progression, and its disruption provides a promising therapeutic strategy. Full article