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Immunology Jan 2023Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and...
Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG and MOG experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE-515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE-515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE-515 blocks activation-induced B and T cell proliferation and MOG -specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG -specific lymphocyte activation-induced proliferation.
Topics: Animals; Mice; Multiple Sclerosis; Deoxycytidine Kinase; Encephalomyelitis, Autoimmune, Experimental; Lymphocytes; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 35986643
DOI: 10.1111/imm.13569 -
Cancer Drug Resistance (Alhambra,... 2020Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, the development of chemoresistance limits its effectiveness. Gemcitabine... (Review)
Review
Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers. However, the development of chemoresistance limits its effectiveness. Gemcitabine resistance is regulated by various factors, including aberrant genetic and epigenetic controls, metabolism of gemcitabine, the microenvironment, epithelial-to-mesenchymal transition, and acquisition of cancer stem cell properties. In many situations, results using cell lines offer valuable lessons leading to the first steps of important findings. In this review, we mainly discuss the factors involved in gemcitabine metabolism in association with chemoresistance, including nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ATP-binding cassette transporters, and outline new perspectives for enhancing the efficacy of gemcitabine to overcome acquired chemoresistance.
PubMed: 35582220
DOI: 10.20517/cdr.2020.39 -
Acta Pharmaceutica Sinica. B Jul 2019Precision medicine is a rapidly-developing modality of medicine in human healthcare. Based on each patient׳s unique characteristics, more accurate dosages and drug... (Review)
Review
Precision medicine is a rapidly-developing modality of medicine in human healthcare. Based on each patient׳s unique characteristics, more accurate dosages and drug selection can be made to achieve better therapeutic efficacy and less adverse reactions in precision medicine. A patient׳s individual parameters that affect drug transporter action can be used to develop a precision medicine guidance, due to the fact that therapeutic efficacy and adverse reactions of drugs can both be affected by expression and function of drug transporters on the cell membrane surface. The purpose of this review is to summarize unique characteristics of human breast cancer resistant protein (BCRP) and the genetic variability in the BCRP encoded gene in the development of precision medicine. Inter-individual variability of BCRP/ can impact choices and outcomes of drug treatment for several diseases, including cancer chemotherapy. Several factors have been implicated in expression and function of BCRP, including genetic, epigenetic, physiologic, pathologic, and environmental factors. Understanding the roles of these factors in controlling expression and function of BCRP is critical for the development of precision medicine based on BCRP-mediated drug transport.
PubMed: 31384528
DOI: 10.1016/j.apsb.2019.01.007 -
International Journal of Molecular... Aug 2023The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human...
The aryl hydrocarbon receptor (AHR) is a transcription factor that is commonly upregulated in pancreatic ductal adenocarcinoma (PDAC). AHR hinders the shuttling of human antigen R (ELAVL1) from the nucleus to the cytoplasm, where it stabilises its target messenger RNAs (mRNAs) and enhances protein expression. Among these target mRNAs are those induced by gemcitabine. Increased AHR expression leads to the sequestration of ELAVL1 in the nucleus, resulting in chemoresistance. This study aimed to investigate the interaction between AHR and ELAVL1 in the pathogenesis of PDAC in vitro. and genes were silenced by siRNA transfection. The RNA and protein were extracted for quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) analysis. Direct binding between the ELAVL1 protein and mRNA was examined through immunoprecipitation (IP) assay. Cell viability, clonogenicity, and migration assays were performed. Our study revealed that both AHR and ELAVL1 inter-regulate each other, while also having a role in cell proliferation, migration, and chemoresistance in PDAC cell lines. Notably, both proteins function through distinct mechanisms. The silencing of ELAVL1 disrupts the stability of its target mRNAs, resulting in the decreased expression of numerous cytoprotective proteins. In contrast, the silencing of diminishes cell migration and proliferation and enhances cell sensitivity to gemcitabine through the AHR-ELAVL1-deoxycytidine kinase (DCK) molecular pathway. In conclusion, AHR and ELAVL1 interaction can form a negative feedback loop. By inhibiting AHR expression, PDAC cells become more susceptible to gemcitabine through the ELAVL1-DCK pathway.
Topics: Humans; Carcinoma, Pancreatic Ductal; ELAV-Like Protein 1; Gemcitabine; Pancreas; Pancreatic Hormones; Pancreatic Neoplasms; Receptors, Aryl Hydrocarbon; RNA, Messenger; Deoxycytidine Kinase
PubMed: 37685961
DOI: 10.3390/ijms241713155 -
Genes Oct 2022Hepatocellular carcinoma (HCC) originates from the hepatocytes and accounts for 90% of liver cancer. The study intends to identify novel prognostic biomarkers for...
BACKGROUND
Hepatocellular carcinoma (HCC) originates from the hepatocytes and accounts for 90% of liver cancer. The study intends to identify novel prognostic biomarkers for predicting the prognosis of HCC patients based on TCGA and GSE14520 cohorts.
METHODS
Differential analysis was employed to obtain the DEGs (Differentially Expressed Genes) of the TCGA-LIHC-TPM cohort. The lasso regression analysis was applied to build the prognosis model through using the TCGA cohort as the training group and the GSE14520 cohort as the testing group. Next, based on the prognosis model, we performed the following analyses: the survival analysis, the independent prognosis analysis, the clinical feature analysis, the mutation analysis, the immune cell infiltration analysis, the tumor microenvironment analysis, and the drug sensitivity analysis. Finally, the survival time of HCC patients was predicted by constructing nomograms.
RESULTS
Through the lasso regression analysis, we obtained a prognosis model of ten genes including (baculoviral IAP repeat containing 5), (cyclin-dependent kinase 4), (deoxycytidine kinase), (heat shock protein family A member 4), (heat shock protein 90 α family class A member 1), (Proteasome 26S Subunit Ubiquitin Receptor, Non-ATPase 2), (interleukin 1 receptor antagonist), (placental growth factor), (secreted phosphoprotein 1), and (stanniocalcin 2). First, we found that the risk score is an independent prognosis factor and is related to the clinical features of HCC patients, covering AFP (α-fetoprotein) and stage. Second, we observed that the mutation was the most obvious mutation between the high-risk and low-risk groups. Third, we also discovered that the risk score is related to some immune cells, covering B cells, T cells, dendritic, macrophages, neutrophils, etc. Fourth, the high-risk group possesses a lower TIDE score, a higher expression of immune checkpoints, and higher ESTIMATE score. Finally, nomograms include the clinical features and risk signatures, displaying the clinical utility of the signature in the survival prediction of HCC patients.
CONCLUSIONS
Through the comprehensive analysis, we constructed an immune-related prognosis model to predict the survival of HCC patients. In addition to predicting the survival time of HCC patients, this model significantly correlates with the tumor microenvironment. Furthermore, we concluded that these ten immune-related genes (, , , , , , , , , and ) serve as novel targets for antitumor immunity. Therefore, this study plays a significant role in exploring the clinical application of immune-related genes.
Topics: Female; Humans; alpha-Fetoproteins; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cyclin-Dependent Kinase 4; Deoxycytidine Kinase; Heat-Shock Proteins; Kaplan-Meier Estimate; Liver Neoplasms; Osteopontin; Placenta Growth Factor; Proteasome Endopeptidase Complex; Receptors, Interleukin-1; Tumor Suppressor Protein p53; Ubiquitins
PubMed: 36292719
DOI: 10.3390/genes13101834 -
Cell Death & Disease May 2024
PubMed: 38821944
DOI: 10.1038/s41419-024-06628-3 -
Journal of Clinical Laboratory Analysis Nov 2020Several biomarkers of gemcitabine effectiveness have been studied in cancers, but less so in hepatocellular carcinoma (HCC), which is identified as the fifth most common...
BACKGROUND
Several biomarkers of gemcitabine effectiveness have been studied in cancers, but less so in hepatocellular carcinoma (HCC), which is identified as the fifth most common cancer worldwide. Investigation of human equilibrative nucleoside transporter-1 (HENT-1) and deoxycytidine kinase (DCK), genes involved in gemcitabine uptake and metabolism, can be beneficial in the selection of potential cancer patients who could be responding to the treatment.
AIM
To study HENT-1 and DCK gene expression in HCC patients with different protocols of treatment.
METHODS
Using real-time PCR, we analyzed expression levels of HENT-1 and DCK genes from peripheral blood samples of 109 patients (20 controls & 89 HCC patients) between March 2015 and March 2017. All the 89 HCC patients received the antioxidants selenium (Se) and vitamin E (Vit.E) either alone (45 patients) or in combination with gemcitabine (24 patients) or radiofrequency ablation (RFA) (20 patients).
RESULTS
There was a significant increase in HENT-1 expression levels in HCC patients treated with Se and Vit.E alone as compared to controls (P ˂ .0001), while there was no significant difference between HCC patients treated with gemcitabine or RFA as compared to controls. In contrast, expression of DCK was significantly increased in all groups of HCC patients as compared to controls (P ˂ .0001).
CONCLUSIONS
HENT-1 and DCK mRNA expressions are important markers of HCC and for GEM effect and GEM sensitivity in patients with HCC. This could be beneficial in the selection of HCC patients sensitive to gemcitabine to avoid subjecting resistant patients to unnecessary chemotherapy.
Topics: Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Cross-Sectional Studies; Deoxycytidine; Deoxycytidine Kinase; Egypt; Equilibrative Nucleoside Transporter 1; Female; Humans; Liver Neoplasms; Male; Real-Time Polymerase Chain Reaction; Treatment Outcome; Gemcitabine
PubMed: 32671914
DOI: 10.1002/jcla.23457 -
Biochemical Pharmacology Feb 2020Deoxycytidine kinase (dCK) is an essential enzyme for production of nucleotides via the salvage pathway; DI-87 is a novel dCK inhibitor in preclinical development for...
BACKGROUND
Deoxycytidine kinase (dCK) is an essential enzyme for production of nucleotides via the salvage pathway; DI-87 is a novel dCK inhibitor in preclinical development for use in anticancer therapy. The current study utilizes PET imaging to evaluate PK-PD relationships and to determine optimal dosing of the drug.
METHODS
NSG mice bearing CEM tumors had plasma and tumor PK assessed using mass spectrometry following oral administration of DI-87. dCK inhibition was assessed after a single dose of oral DI-87 followed by a [F]CFA PET probe and PET imaging. Tumor growth inhibition was assessed by orally administering DI-87 with concurrent intraperitoneal thymidine.
RESULTS
DI-87 had an in vitro EC of 10.2 nM with low protein binding. Peak DI-87 concentrations were observed between 1-3 h and 3-9 h in plasma and tumor, respectively, with tumor concentrations less than one third of plasma. Full dCK inhibition, as evaluated by PET imaging, was observed as early as 3 h following 25 mg/kg dosing and was maintained for 12 h, with full recovery of enzyme activity after 36 h. When DI-87 was administered as repeated doses in combination with thymidine, full dCK inhibition was maintained at 12 h (25 mg/kg twice daily dose) and led to maximal tumor growth inhibition.
CONCLUSIONS
DI-87 is a promising new compound for use in combination therapy against tumors expressing dCK. Utilizing a [F]CFA PET probe targeting the pathway of interest allowed for efficient and accurate identification of the optimal dose for growth inhibition.
Topics: Animals; Antineoplastic Agents; Cell Line; Cell Proliferation; Deoxycytidine Kinase; Dose-Response Relationship, Drug; Drug Therapy, Combination; Gene Expression Regulation, Enzymologic; Humans; Male; Mice; Molecular Structure; Neoplasms, Experimental
PubMed: 31812677
DOI: 10.1016/j.bcp.2019.113742 -
Oncogene Sep 2021Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged...
Pancreatic cancer (PC) remains a major cause of cancer-related deaths primarily due to its inherent potential of therapy resistance. Checkpoint inhibitors have emerged as promising anti-cancer agents when used in combination with conventional anti-cancer therapies. Recent studies have highlighted a critical role of the Greatwall kinase (microtubule-associated serine/threonine-protein kinase-like (MASTL)) in promoting oncogenic malignancy and resistance to anti-cancer therapies; however, its role in PC remains unknown. Based on a comprehensive investigation involving PC patient samples, murine models of PC progression (Kras;PdxCre-KC and Kras;p53;PdxCre-KPC), and loss and gain of function studies, we report a previously undescribed critical role of MASTL in promoting cancer malignancy and therapy resistance. Mechanistically, MASTL promotes PC by modulating the epidermal growth factor receptor protein stability and, thereupon, kinase signaling. We further demonstrate that combinatorial therapy targeting MASTL promotes the efficacy of the cell-killing effects of Gemcitabine using both genetic and pharmacological inhibitions. Taken together, this study identifies a key role of MASTL in promoting PC progression and its utility as a novel target in promoting sensitivity to the anti-PC therapies.
Topics: Animals; Cell Line, Tumor; Deoxycytidine; Disease Progression; ErbB Receptors; Gain of Function Mutation; Gene Expression Regulation, Neoplastic; Humans; Loss of Function Mutation; Mice; Microtubule-Associated Proteins; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Protein Stability; Signal Transduction; Up-Regulation; Gemcitabine
PubMed: 34331012
DOI: 10.1038/s41388-021-01951-x -
Advanced Science (Weinheim,... Jul 2021Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A...
Because there is no effective treatment for late-stage prostate cancer (PCa) at this moment, identifying novel targets for therapy of advanced PCa is urgently needed. A new network-based systems biology approach, XDeath, is developed to detect crosstalk of signaling pathways associated with PCa progression. This unique integrated network merges gene causal regulation networks and protein-protein interactions to identify novel co-targets for PCa treatment. The results show that polo-like kinase 1 (Plk1) and DNA methyltransferase 3A (DNMT3a)-related signaling pathways are robustly enhanced during PCa progression and together they regulate autophagy as a common death mode. Mechanistically, it is shown that Plk1 phosphorylation of DNMT3a leads to its degradation in mitosis and that DNMT3a represses Plk1 transcription to inhibit autophagy in interphase, suggesting a negative feedback loop between these two proteins. Finally, a combination of the DNMT inhibitor 5-Aza-2'-deoxycytidine (5-Aza) with inhibition of Plk1 suppresses PCa synergistically.
Topics: Animals; Cell Cycle Proteins; DNA Methyltransferase 3A; Disease Models, Animal; Humans; Male; Mice; Prostatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Signal Transduction; Polo-Like Kinase 1
PubMed: 34051063
DOI: 10.1002/advs.202101458