Current Cancer Drug Targets - Online First

This study aims to explore the potential mechanisms by which Raddeanoside R13 (R13) inhibits the proliferation, invasion, and metastasis of gastric cancer (GC) cells through network pharmacology analysis and experimental validation.

First, network pharmacology was used to explore the potential mechanisms of R13 in treating GC. The effects of R13 on GC cell proliferation were assessed using CCK-8 and colony formation assays. Apoptosis was measured by flow cytometry, while the effects of R13 on invasion and metastasis were evaluated through wound healing and Transwell invasion assays. Finally, Western blotting was performed to investigate the impact of R13 on the expression of epithelial-to-mesenchymal transition (EMT) markers, PI3K/AKT signaling pathway proteins, and apoptosis-related proteins in GC cells.

A total of 58 potential targets of R13 in the treatment of GC were identified. R13 was found to affect the development of GC by regulating pathways, such as NFKB1, mTOR, apoptosis, and the PI3K-AKT signaling pathway. In vitro experiments confirmed that R13 inhibited the proliferation, invasion, and metastasis of GC cells while promoting apoptosis. Additionally, we found that R13 suppressed the EMT of GC cells and reduced the phosphorylation levels of PI3K, AKT, and mTOR. When this pathway was activated, it partially reversed these effects.

R13 inhibited the proliferation, invasion, and metastasis of GC cells while inducing apoptosis. Furthermore, R13 may suppress the EMT process in GC cells by inhibiting the PI3K/AKT/mTOR signaling pathway. These findings provide a foundation for the potential use of R13 as a therapeutic strategy for GC.

The role of Trimethylamine N-oxide (TMAO) in oocyte maturation and embryogenesis remains unclear, particularly its impact on ovarian granulosa cells (OGCs) and its underlying mechanisms.

This study examined the effects of TMAO (100-400 µmol/L) on oocyte maturation, cumulus cell expansion, mitochondrial distribution, and embryonic development in vitro and in a BALB/c mouse model. The involvement of the NF-κB/NLRP3 signaling pathway in TMAO-induced ovarian dysfunction was assessed using Western blotting and gene expression analyses. The potential therapeutic effect of miRNA-146, an NF-κB inhibitor, was also explored.

Western blotting confirmed that TMAO activates the NF-κB signaling pathway and induces the synthesis of caspase 3 and NLRP3 complexes. However, pretreatment with miRNA-146, an NF-κB inhibitor, significantly reduced inflammation and inflammatory gene expression during TMAO therapy. Additionally, miRNA-146 pretreatment promoted oocyte maturation by suppressing NF-κB/NLRP3 activation, OGCs apoptotic inflammatory factor expression, and the gene expression of NF-κB, caspase 3, and NLRP3.

Findings demonstrate that TMAO disrupts oocyte development through NF-κB/NLRP3 activation, contributing to ovarian dysfunction. Notably, targeting TMAO and its downstream signaling could serve as a novel therapeutic strategy for premature ovarian insufficiency (POI).

Lung cancer is the most commonly diagnosed cancer type and the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer cases and includes two main subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Understanding the differences in genes causing the proliferation of LUAD and LUSC is key to advancing the diagnosis and targeted treatment development.

The aim of this study was to identify candidate genes and potential tumorigenesis mechanisms distinguishing LUAD and LUSC.

Three pooled transcriptomic datasets (GSE10245, GSE37745, and GSE43580) were analyzed from the Gene Expression Omnibus (GEO) database, with each dataset statistically tested for differentially expressed genes (DEGs). DEGs between lung LUAD and LUSC of the three datasets were analyzed with Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A protein-protein interaction (PPI) network was constructed to screen candidate genes.

This study identified 138 shared DEGs among three patient-level gene expression datasets, containing 39 upregulated genes and 99 downregulated genes. The GO and KEGG enrichment analysis results showed the functions of DEGs to be mainly associated with epidermis development, cornified envelope, structural constituent of epidermis, and estrogen signaling pathway. Finally, through the PPI network, eight core genes were identified, including KRT14, KRT5, KRT6A, KRT16, SPRR1A, SPRR1B, SPRR3, and KRT6B.

We have elucidated key genes and molecular mechanisms linked to NSCLC subtypes. These findings have the potential to facilitate improved diagnostic and therapeutic targets for LUAD and LUSC biomarkers.

This study aims to provide a comprehensive understanding of the crucial role of MCM4 in melanoma progression regarding the regulatory communication between macrophages and cancer cells mediated by extracellular vesicles.

Initially, a preliminary analysis was conducted using the Tumor Immune Estimation Resource (TIMER) database. Subsequently, the role of MCM4 knockdown on the polarization of THP-1 and RAW264.7 macrophages was observed. Finally, the biological functionalities of exosomes derived from A375 cells overexpressing MCM4 on normal melanocytes (HEM-L) were explored.

On the one hand, MCM4 knockdown resulted in the upregulation of M1 macrophage markers and downregulation of M2 macrophage markers, indicating that MCM4 could facilitate polarization of macrophages toward the M2 phenotype and suggesting its oncogenic potential. On the other hand, MCM4 overexpression in melanocytes increased the secretion of exosomes, enhancing the proliferation, clonogenic, and DNA synthesis abilities of normal melanocytes. In addition, MCM4 overexpression-induced secretion of exosomes promoted the migration and invasion capabilities of normal melanocytes.

Exosomes secreted by MCM4-overexpressed melanocytes could stimulate their proliferation, migration, and invasion abilities. MCM4 promoted M2 polarization of macrophages, indicating its crucial role in tumor microenvironment formation and thereby facilitating tumor development.

HER2 exon 20 insertions exhibit relative resistance to chemotherapy and covalent HER2-targeted tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Furthermore, specific missense mutations in the extracellular domain of the HER2 protein have been identified as oncogenic drivers in NSCLC. However, their structural properties and clinical response to HER2-targeted inhibitors remain poorly understood, warranting further investigation. R456C represents a rare exon 12 missense mutation in the HER2 extracellular domain, with limited documentation in NSCLC.

This study presents an atypical case of NSCLC with a HER2 R456C mutation, where the patient experienced a favorable response and substantial survival benefit from the HER2-targeted inhibitor pyrotinib. A patient, a 65-year-old man diagnosed with stage IIIB lung adenocarcinoma, initially underwent radical concurrent chemoradiotherapy. Upon disease recurrence, polymerase chain reaction assay detected no oncogenic alterations, and programmed cell death ligand 1 (PD-L1) expression was negative. Chemotherapy in combination with bevacizumab resulted in stable disease, providing a progression-free survival (PFS) benefit of 6 months. However, anlotinib proved ineffective against brain metastasis, necessitating brain radiotherapy. A subsequent lung biopsy confirmed adenocarcinoma and next-generation sequencing identified a somatic HER2 exon 12 missense mutation, p.R456C. Following pyrotinib administration, the patient’s pulmonary metastases significantly diminished, and the brain metastasis regressed, resulting in a partial response and a PFS benefit of 13 months.

To the best of our knowledge, this study represents the first reported case demonstrating the promising efficacy of pyrotinib in HER2-altered NSCLC harboring the rare exon 12 R456C mutation. Heterogeneous alterations in the HER2 extracellular segment, such as R456C, may be targetable and could confer survival benefits with HER2-targeted inhibitors.

This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.

In vitro experiments were conducted to explore the effects of ARG on the biological behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autophagy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were assessed.

CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. Western blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax increased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mitochondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmission electron microscopy. ARG inhibited the proliferation and induced the apoptosis of melanoma cells in vivo.

Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.

This comprehensive assessment and quantitative synthesis aimed to assess the effectiveness and safety profile of pembrolizumab, an antagonist of the programmed cell death protein 1 [PD-1] pathway, for individuals with metastatic colorectal carcinoma [mCRC].

A comprehensive search of scholarly articles was performed using the PubMed and Web of Science [WOS] databases from January 2015 to August 2024. The scope of the search was limited to randomized controlled trials and clinical studies that reported the effectiveness of pembrolizumab in patients with metastatic colorectal cancer [mCRC], which emphasized critical indicators, such as overall survival, progression-free survival, objective response rate, and disease control rate. The research also considered secondary outcomes, including the incidence of severe adverse events and mortality rates. Data extraction was performed by two independent reviewers, who employed a standardized data collection form. The subsequent meta-analysis was performed using RevMan 5.0, a software tool for statistical analysis.

Six studies with 1,634 patients were included, and of these patients, 812 were in the pembrolizumab group, and 822 were in the control group. The results of the meta-analysis indicated via the standard mean difference [SMD] that the overall survival [OS] of patients in the pembrolizumab group was significantly different from that of patients in the control group [SMD = 0.21, 95% CI [0.09, 0.32], P = 0.0005]. The progression-free survival [PFS] of patients in the pembrolizumab group was slightly longer than that of patients in the control group according to the SMD, and this difference was statistically significant [SMD = 0.11, 95% CI [0.01, 0.22], P = 0.03]. Compared with the objective response rate [ORR] of patients in the control group, that of patients in the pembrolizumab group was significantly higher [OR = 1.71, 95% CI [1.34, 2.17], P < 0.0001]. The mortality rate in the pembrolizumab group was also significantly different from that in the control group [OR = 0.67, 95% CI [0.52, 0.87], P = 0.002].

Pembrolizumab may help improve overall survival [OS] and progression-free survival [PFS] in patients with metastatic colorectal cancer, which can potentially reduce the mortality rate. More research using larger, well-designed studies is needed to further confirm these findings.

Yippee Like 1 (YPEL1) is a nuclear protein involved in various cellular processes, including cell cycle regulation, senescence, and mammalian development. It plays a dual role in cancer, functioning as either an antitumor or tumor-promoting factor.

We assessed the RNA and protein levels of YPEL1 in both NK/T-cell,lymphoma cell lines and gemcitabine-resistant lymphoma cells using qPCR and western blot, respectively. Flow cytometry was employed to analyze cellular apoptosis and the cell cycle. The impact of YPEL1 knockdown on the proliferation of NK/T-cell lymphoma cells was evaluated through CCK8 assay and a xenograft model, while transcriptomic analysis was conducted to explore the cellular signaling pathways influenced by YPEL1 silencing.

In the current study, via The Cancer Genome Atlas (TCGA) search, we found that YPEL1 is aberrantly expressed in various cancers. High expression of YPEL1 correlated with poorer survival outcomes, whereas low expression of YPEL1 was associated with improved overall survival of patients. YT cell lines and gemcitabine-resistant YT cell line (YT/Gem-R) exhibit elevated levels of the YPEL1 protein

These findings suggest that YPEL1 exhibits the potential for being used as a target for NK / T cell lymphoma treatment.

Prior research has demonstrated that proteins play a significant role in the prognosis and treatments of various sarcomas, including Ewing sarcoma through the interplay of downstream signaling cascades. However, there is limited understanding about the strcucture conformation of EWSR1 and its structural implication in the prognosis of Ewsing Sarcoma by interaction with RNA molecules.

The primary goal of ongoing research is to determine how EWSR1 contributes to Ewing sarcoma.

The current study explores the complexity of EWSR1 structure and its conformational interactions with RNA in relation to Ewing sarcoma.

Here, we employed a comparative modeling approach to predict EWSR1 domains separately and assembled them into one structural unit using a DEMO server. Additionally, the RNA motifs interacting with EWSR1 were predicted, and the 3D model was built using RNAComposer. Protein-RNA docking and MD simulation studies were carried out to check the intermolecular interactions and stability behavior of docked EWSR1-RNA complexes.

The overall results explore the structural insights into EWSR1 and their interactions with RNA, which may play a momentous role in co- and post-transcriptional regulation to control gene expression.

Taken togather, our findings suggest that EWSR1 may be a useful therapeutic target for the diagnosis and management of Ewing sarcoma.