Current Cancer Drug Targets - Volume 25, Issue 3, 2025

UMP-CMP kinase 2 (CMPK2) is involved in mitochondrial DNA synthesis, which can be oxidized and released into the cytoplasm in innate immunity. It initiates the assembly of NLRP3 inflammasomes and mediates various pathological processes such as human immunodeficiency virus infection and systemic lupus erythematosus. However, the role of CMPK2 in tumor progression and tumor immunity remains unclear.

We identified CMPK2 expression patterns in the Genotype Tissue-Expression (GTEx), The Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia (CCLE) databases. Validation was performed using immunohistochemical staining data from the Human Protein Atlas (HPA) database and qPCR experiments. Receiver operating characteristic curve analysis and Kaplan-Meier survival analysis were conducted to assess the clinical relevance of CMPK2 expression. The Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) algorithm and the Tumor IMmune Estimation Resource (TIMER) database were used to evaluate the correlation between CMPK2 and immune infiltration in tumors. The Tumor Immune Syngeneic Mouse (TISMO) database and other public datasets were utilized to assess the impact of CMPK2 on immune therapy response. MEXPRESS and MethSurv databases were employed to investigate the effects of methylation on CMPK2 expression.

CMPK2 expression was elevated in 23 cancers and decreased in two cancers. Furthermore, CMPK2 expression had a high diagnostic value for 16 cancers. Elevated CMPK2 expression was associated with lower overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in four cancers. Immune microenvironment-related analysis revealed strong associations between CMPK2 expression and immune cell infiltration, as well as immune checkpoint expression across various tumors. Notably, in four mouse immunotherapy cohorts, CMPK2 expression in treated mouse tumors was higher post-treatment. In five clinical immunotherapy cohorts, patients with high CMPK2 expression show better responses to immunotherapy. Moreover, the methylation level of CMPK2 gene was closely correlated to its expression and tumor prognosis. Among these cancers, the clinical and immunological indications of skin cutaneous melanoma (SKCM) are particularly closely related to CMPK2 expression.

Our analysis preliminarily describes the complex function of CMPK2 in cancer progression and immune microenvironment, highlighting its potential as a diagnostic and therapeutic target for immunotherapy.

Human cervix adenocarcinoma (CC) caused by papillomavirus is the third most common cancer among female malignant tumors. Bioactive compounds such as cyclodipeptides (CDPs) possess cytotoxic effects in human cervical cancer HeLa cells mainly by blocking the PI3K/Akt/mTOR pathway and subsequently inducing gene expression by countless transcription regulators. However, the upstream elements of signaling pathways have not been well studied.

To elucidate the cytotoxic and antiproliferative responses of the HeLa cell line to CDPs by a transcriptomic analysis previously carried out, we identified by immunochemical analyses, differential expression of genes related to the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/MET) receptors. Furthermore, molecular docking was carried out to evaluate the interactions of CDPs with the EGF and MET substrate binding sites.

Immunochemical and molecular docking analyses suggest that the HGF/MET receptor participation in CDPs cytotoxic effect was independent of the protein expression levels. However, protein modulation of downstream Met-targets occurred due to the inhibition of phosphorylation of the HGF/MET receptor. Results suggest that the antiproliferative and cytotoxicity of CDPs in HeLa cells involve the HGF/MET receptor upstream of PI3K/Akt/mTOR pathway; assays with the human breast cancer MCF-7 and MDA-MB-231cell lines supported the finding.

Data provide new insights into the molecular mechanisms involved in CDPs cytotoxicity and antiproliferative effects, suggesting that the signal transduction mechanism may be related to the inhibition of the phosphorylation of the EGF/MET receptor at the level of substrate binding site by an inhibition mechanism similar to that of Gefitinib and Foretinib anti-neoplastic drugs.

It remains controversial whether the current subtypes of kidney renal papillary cell carcinoma (KIRP) can be used to predict the prognosis independently.

This observational study aimed to identify a risk signature based on necroptotic process-related genes (NPRGs) in KIRP.

In the training cohort, LASSO regression was applied to construct the risk signature from 158 NPRGs, followed by the analysis of Overall Survival (OS) using the Kaplan-Meier method. The signature accuracy was evaluated by the Receiver Operating Characteristic (ROC) curve, which was further validated by the test cohort. Wilcoxon test was used to compare the expressions of immune-related genes, neoantigen genes, and immune infiltration between different risk groups, while the correlation test was performed between NPRGs expressions and drug sensitivity. Gene set enrichment analysis was used to investigate the NPRGs' signature’s biological functions.

We finally screened out 4-NPRGs (BIRC3, CAMK2B, PYGM, and TRADD) for constructing the risk signature with the area under the ROC curve (AUC) reaching about 0.8. The risk score could be used as an independent OS predictor. Consistent with the enriched signaling, the NPRGs signature was found to be closely associated with neoantigen, immune cell infiltration, and immune-related functions. Based on NPRGs expressions, we also predicted multiple drugs potentially sensitive or resistant to treatment.

The novel 4-NPRGs risk signature can predict the prognosis, immune infiltration, and therapeutic sensitivity of KIRP.

Doxorubicin (DOX) is a chemotherapy drug that is widely used in cancer therapy, especially in Triple-Negative Breast Cancer (TNBC) patients. Nevertheless, cytoprotective autophagy induction by DOX limits its cytotoxic effect and drug resistance induction in patients. Therefore, finding a new way is essential for increasing the effectiveness of this drug for cancer treatment.

This study aimed to investigate the effect of L-lysine on DOX cytotoxicity, probably through autophagy modulation in TNBC cell lines.

We used two TNBC cell lines, MDA-MB-231 and MDA-MB-468, with various levels of autophagy activity. Cell viability after treatment with L-lysine alone and in combination therapy was evaluated by MTT assay. Reactive Oxygen Species (ROS), nitric oxide (NO) concentration, and arginase activity were assessed using flow cytometric analysis, Griess reaction, and arginase activity assay kit, respectively. Real-time PCR and western blot analysis were used to evaluate the L-lysine effect on the autophagy-related genes and protein expression. Cell cycle profile and apoptotic assay were performed using flow cytometric analysis.

The obtained data indicated that L-lysine in both concentrations of 24 and 32 mM increased the autophagy flux and enhanced the DOX cytotoxicity, especially in MDA-MB-231, which demonstrated higher autophagy activity than MDA-MB-468, by inducing ROS and NO production. Furthermore, L-lysine induced G2/M arrest autophagy cell death, while significant apoptotic changes were not observed.

These findings suggest that L-lysine can increase DOX cytotoxicity through autophagy modulation. Thus, L-lysine, in combination with DOX, may facilitate the development of novel adjunct therapy for cancer.

Glioblastoma multiforme (GBM), the most prevalent form of central nervous system (CNS) cancer, stands as a highly aggressive glioma deemed virtually incurable according to the World Health Organization (WHO) standards, with survival rates typically falling between 6 to 18 months. Despite concerted efforts, advancements in survival rates have been elusive. Recent cutting-edge research has unveiled bionanocatalysts with 1% Pt, demonstrating unparalleled selectivity in cleaving C-C, C-N, and C-O bonds within DNA in malignant cells. The application of these nanoparticles has yielded promising outcomes.

The objective of this study is to employ bionanocatalysts for the treatment of Glioblastoma Multiforme (GBM) in a patient, followed by the evaluation of obtained tissues through electronic microscopy.

Bionanocatalysts were synthesized using established protocols. These catalysts were then surgically implanted into the GBM tissue through stereotaxic procedures. Subsequently, tissue samples were extracted from the patient and meticulously examined using Scanning Electron Microscopy (SEM).

Detailed examination of biopsies via SEM unveiled a complex network of small capillaries branching from a central vessel, accompanied by a significant presence of solid carbonate formations. Remarkably, the patient subjected to this innovative approach exhibited a three-year extension in survival, highlighting the potential efficacy of bionanocatalysts in combating GBM and its metastases.

Bionanocatalysts demonstrate promise as a viable treatment option for severe cases of GBM. Additionally, the identification of solid calcium carbonate formations may serve as a diagnostic marker not only for GBM but also for other CNS pathologies.

Lung cancer is a highly prevalent tumor with a lack of biological markers that reflect its progression. Mast cell surface membrane protein 1 (MCEMP1, also known as C19ORF59) has not been reported in lung adenocarcinoma (LUAD).

We aimed to investigate the role of MCEMP1 in LUAD.

MCEMP1 expression in LUAD was analyzed using The Cancer Genome Atlas (TCGA) data, and conducted univariate and multivariate Cox regression analyses to evaluate the prognostic significance of MCEMP1 expression in TCGA. Tumor Immune Estimation Resource (TIMER) was used for examining the correlation between MCEMP1 expression and immune cell infiltration in LUAD. Furthermore, proliferation, migration, invasion, and colony-forming ability were investigated using LUAD cell lines.

MCEMP1 expression in LUAD patient tissues and was correlated with lymph node metastasis, differentiation level, and tumor status. The Area under Curve (AUC) value of MCEMP1 for the Receiver Operating Characteristic (ROC) curve analysis was 0.984. The immune infiltration analysis revealed a correlation between MCEMP1 expression and the extent of macrophages and neutrophil infiltration in LUAD. Additionally, MCEMP1 has low expression in clinical samples, MCEMP1 overexpressed in LUAD cells substantially reduced cell growth, migration, and invasion of malignant cells.

Low expression MCEMP1 promotes LUAD progression, which provides new insights and a potential biological target for future LUAD therapies.

Lung cancer remains a major global health threat due to its complex microenvironment, particularly the role of neutrophils, which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer progression.

Employing in vitro experimental models, this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-γ secretion, apoptosis, PD-L1 expression, and T-cell proliferation by using techniques, such as ELISA, flow cytometry, immunofluorescence, and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and PD-L1.

Lung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils, increased PD-L1 expression, and suppressed T-cell proliferation and IFN-γ secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS), while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally, CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell proliferation.

This study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors, such as IL-8, thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.

The purpose of this study was to investigate the role of DGUOK in the progression of colorectal cancer (CRC) and its impact on the sensitivity of CRC cells to 5-FU treatment.

We conducted bioinformatics analysis and qRT-PCR to evaluate DGUOK expression in CRC tissues/cells. Cell viability of CRC cells treated with 5-FU was assessed using CCK-8 and colony formation assays. Autophagy levels were determined through immunofluorescence assays and Western blot analysis. Additionally, the influence of p-p38 on autophagy was investigated via Western blotting. A rescue assay was performed to confirm whether DGUOK/p38 affects 5-FU sensitivity in CRC cells through autophagy.

Our findings indicate that DGUOK is upregulated in CRC tissues compared to normal tissues, correlating with increased cell proliferation and migration. Functionally, inhibition of DGUOK enhances autophagy, thereby decreasing the sensitivity of CRC cells to 5-FU. This effect is partly mediated by DGUOK's impact on the mitogen-activated protein kinase (MAPK) pathway, specifically promoting the phosphorylation of p38 MAPK, a crucial regulator in autophagy pathways.

These results suggest that DGUOK could serve as a novel marker for predicting the efficacy of 5-FU in CRC treatment.