Comprehensive analysis of 33 human cancers reveals clinical implications and immunotherapeutic value of the solute carrier family 35 member A2.

Background: Solute carrier family 35 member A2 (SLC35A2), which belongs to the SLC35 solute carrier family of human nucleoside sugar transporters, has shown regulatory roles in various tumors and neoplasms. However, the function of SLC35A2 across human cancers remains to be systematically assessed. Insights into the prediction ability of SLC35A2 in clinical practice and immunotherapy response remains limited. Materials and methods: We obtained the gene expression and protein levels of SLC35A2 in a variety of tumors from Molecular Taxonomy of Breast Cancer International Consortium, The Cancer Genome Atlas, Gene Expression Omnibus, Chinese Glioma Genome Atlas, and Human Protein Atlas databases. The SLC35A2 level was validated by immunohistochemistry. The predictive value for prognosis was evaluated by Kaplan-Meier survival and Cox regression analyses. Correlations between SLC35A2 expression and DNA methylation, genetic alterations, tumor mutation burden (TMB), microsatellite instability (MSI), and tumor microenvironment were performed using Spearman's correlation analysis. The possible downstream pathways of SLC35A2 in different human cancers were explored using gene set variation analysis. The potential role of SLC35A2 in the tumor immune microenvironment was evaluated via EPIC, CIBERSORT, MCP-counter, CIBERSORT-ABS, quanTIseq, TIMER, and xCell algorithms. The difference in the immunotherapeutic response of SLC35A2 under different expression conditions was evaluated by the tumor immune dysfunction and exclusion (TIDE) score as well as four independent immunotherapy cohorts, which includes patients with bladder urothelial carcinoma (BLCA, N = 299), non-small cell lung cancer (NSCLC, N = 72 and N = 36) and skin cutaneous melanoma (SKCM, N = 25). Potential drugs were identified using the CellMiner database and molecular docking. Results: SLC35A2 exhibited abnormally high or low expression in 23 cancers and was significantly associated with the prognosis. In various cancers, SLC35A2 expression and mammalian target of rapamycin complex 1 signaling were positively correlated. Multiple algorithmic immune infiltration analyses suggested an inverse relation between SLC35A2 expression and infiltrating immune cells, which includes CD4+T cells, CD8+T cells, B cells, and natural killer cells (NK) in various tumors. Furthermore, SLC35A2 expression was significantly correlated with pan-cancer immune checkpoints, TMB, MSI, and TIDE genes. SLC35A2 showed significant predictive value for the immunotherapy response of patients with diverse cancers. Two drugs, vismodegib and abiraterone, were identified, and the free binding energy of cytochrome P17 with abiraterone was higher than that of SLC35A2 with abiraterone. Conclusion: Our study revealed that SLC35A2 is upregulated in 20 types of cancer, including lung adenocarcinoma (LUAD), breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), and lung squamous cell carcinoma (LUSC). The upregulated SLC35A2 in five cancer types indicates a poor prognosis. Furthermore, there was a positive correlation between the overexpression of SLC35A2 and reduced lymphocyte infiltration in 13 cancer types, including BRCA and COAD. Based on data from several clinical trials, patients with LUAD, LUSC, SKCM, and BLCA who exhibited high SLC35A2 expression may experience improved immunotherapy response. Therefore, SLC35A2 could be considered a potential predictive biomarker for the prognosis and immunotherapy efficacy of various tumors. Our study provides a theoretical basis for further investigating its prognostic and therapeutic potentials.

An Enzyme-Engineered Nonporous Copper(I) Coordination Polymer Nanoplatform for Cuproptosis-Based Synergistic Cancer Therapy.

Cuproptosis, a newly identified form of regulated cell death that is copper-dependent, offers great opportunities for exploring the use of copper-based nanomaterials inducing cuproptosis for cancer treatment. Here, a glucose oxidase (GOx)-engineered nonporous copper(I) 1,2,4-triazolate ([Cu(tz)]) coordination polymer (CP) nanoplatform, denoted as GOx@[Cu(tz)], for starvation-augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be "turned on" for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@[Cu(tz)]-mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper-induced toxicity. The increased intracellular hydrogen peroxide (H2 O2 ) levels, due to the oxidation of glucose, activates the type I photodynamic therapy (PDT) efficacy of GOx@[Cu(tz)]. The in vivo experimental results indicate that GOx@[Cu(tz)] produces negligible systemic toxicity and inhibits tumor growth by 92.4% in athymic mice bearing 5637 bladder tumors. This is thought to be the first report of a cupreous nanomaterial capable of inducing cuproptosis and cuproptosis-based synergistic therapy in bladder cancer, which should invigorate studies pursuing rational design of efficacious cancer therapy strategies based on cuproptosis.

A Novel Signature Integrated of Immunoglobulin, Glycosylation and Anti-Viral Genes to Predict Prognosis for Breast Cancer.

Background: Aberrant glycosylation is significantly related to the occurrence, progression, metastasis, and drug resistance of tumors. It is essential to identify glycosylation and related genes with prognostic value for breast cancer. Objective: We aimed to construct and validate a prognostic model based on glycosylation and related genes, and further investigate its prognosis values in validation set and external independent cohorts. Materials and Methods: The transcriptome and clinical data of breast cancer patients were downloaded from The Cancer Genome Atlas (TCGA, n = 1072), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1451), and GSE2741 (n = 120). Glycosylation-related genes were downloaded from the Genecards website. Differentially expressed glycosylation-related geneswere identified by comparing the tumor tissues with the adjacent tissues. The TCGA data were randomly divided into training set and validation set in a 1:1 ratio for further analysis. The glycosylation risk-scoring prognosis model was constructed by univariate and multivariate Cox regression analysis, followed by confirmation in TCGA validation, METABRIC, and GEO datasets. Gene set enrichment analysis (GSEA) and Gene ontology analysis for identifying the affected pathways in the high- and low-risk groups were performed. Results: We attained 1072 breast cancer samples from the TCGA database and 786 glycosylation genes from the Genecards website. A signature contains immunoglobulin, glycosylation and anti-viral related genes was constructed to separate BRCA patients into two risk groups. Low-risk patients had better overall survival than high-risk patients (p < 0.001). A nomogram was constructed with risk scores and clinical characteristics. The area under time-dependent ROC curve reached 0.764 at 1 year, 0.744 at 3 years, and 0.765 at 5 years in the training set. Subgroup analysis showed differences in OS between the high- and low-risk patients in different subgroups. Moreover, the risk score was confirmed as an independent prognostic indicator of BRCA patients and was potentially correlated with immunotherapy response and drug sensitivity. Conclusion: We identified a novel signature integrated of immunoglobulin (IGHA2), glycosylation-related (SLC35A2) and anti-viral gene (BST2) that was an independent prognostic indicator for BRCA patients. The risk-scoring model could be used for predicting prognosis and immunotherapy in BRCA, thus providing a powerful instrument for combating BRCA.

The Spleen Tyrosine Kinase Inhibitor, Entospletinib (GS-9973) Restores Chemosensitivity in Lung Cancer Cells by Modulating ABCG2-mediated Multidrug Resistance.

Tyrosine kinase inhibitors (TKIs) are important in managing lymphoid malignancies by targeting B-cell receptor signaling pathways. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase (Syk), currently in the phase II clinical trials for the treatment of chronic lymphocytic leukemia. Syk is abundantly present in the cells of hematopoietic lineage that mediates cell proliferation, differentiation, and adhesion. In this current study, we evaluated the efficacy of GS-9973 to overcome multidrug resistance (MDR) due to the overexpression of the ABCG2 transporter in the non-small cell lung cancer (NSCLC) cell line, NCI-H460/MX20. In vitro, 3 µM of GS-9973 reversed the drug resistance of NCI-H460/MX20 cell line to mitoxantrone or doxorubicin. GS-9973, at 3 µM reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the protein level but did not alter the ABCG2 mRNA expression and subcellular localization of the ABCG2 protein compared to drug-resistant cells incubated with the vehicle. GS-9973 produced a moderate concentration-dependent increase in the ATPase activity of ABCG2 (EC50 = 0.42 µM) and molecular docking data indicated that GS-9973 had a high affinity (-10.226 kcal/mol) for the substrate-binding site of ABCG2. Finally, HPLC analysis proved that the intracellular concentration of GS-9973 is not significantly different in both parental and resistant cell lines. In conclusion, our study suggests that in vitro, GS-9973 in combination with certain anticancer drugs, represent a strategy to overcome ABCG2-mediated MDR cancers.

Overexpression of human ATP-binding cassette transporter ABCG2 contributes to reducing the cytotoxicity of GSK1070916 in cancer cells.

The emergence of multidrug resistance (MDR) is one of the main factors that impair therapeutic outcome in cancer therapy. Among all the factors that contribute to MDR, overexpression of ABCG2 transporter has been described as a key factor. GSK1070916 is a potent Aurora kinase inhibitor with broad anticancer effects. The robust efficacy shown in preclinical studies allowed the drug progress to clinical investigation. However, the potential mechanisms of acquired resistance to GSK1070916 remain inconclusive. Since several Aurora kinase inhibitors were reported to be transported substrates of ABCG2, we aimed to identify the potential interaction of GSK1070916 with ABCG2. Our data showed that ABCG2-overexpressing cells demonstrated high resistance-fold to GSK1070916 compared to the parental cells. In addition, combination of GSK1070916 with an ABCG2 inhibitor was able to restore its sensitivity. The multicellular tumor spheroid assay supported this finding by demonstrating attenuated growth inhibition in ABCG2-overexpressing tumor spheroids. In addition, the ABCG2 ATPase assay and computational modeling suggested that GSK1070916 could bind to ABCG2 substrate-binding site. The HPLC assay provided another direct evidence that ABCG2-overexpressing cells showed attenuated intracellular accumulation of GSK1070916, and such phenomenon was abolished by Ko143, a known ABCG2 inhibitor. Furthermore, GSK1070916 was able to hinder the efflux activity of ABCG2, indicating possible drug-drug interactions with other ABCG2 substrate drugs. In summary, we revealed that overexpression of ABCG2 can cause GSK1070916 resistance in cancer cells. The combination of an ABCG2 inhibitor with GSK1070916 may be a rational strategy to overcome the drug resistance and should be considered for clinical investigation.