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1.
Mol Biol Rep ; 51(1): 671, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38787503

ABSTRACT

BACKGROUND: TRAIL protein on binding to its cognate death receptors (DR) can induce apoptosis specifically in breast tumor cells sparing normal cells. However, TRAIL also binds to decoy receptors (DCR) thereby inhibiting the apoptotic pathways thus causing TRAIL resistance. Also, one of the barriers due to which TRAIL-based therapy could not become FDA-approved might be because of resistance to therapy. Therefore, in the current study we wanted to explore the role of transcription factors in TRAIL resistance with respect to breast cancer. METHODS: Microarray data from TRAIL-sensitive (TS) and TRAIL-resistant (TR) MDA-MB-231 cells were reanalyzed followed by validation of the candidate genes using quantitative PCR (qPCR), immunoblotting and immunofluorescence technique. Overexpression of the candidate gene was performed in MDA-MB-231 and MCF7 cells followed by cell viability assay and immunoblotting for cleaved caspase-3. Additionally, immunoblotting for DCR2 was carried out. TCGA breast cancer patient survival was used for Kaplan-Meier (KM) plot. RESULTS: Validation of the candidate gene i.e. ELF3 using qPCR and immunoblotting revealed it to be downregulated in TR cells compared to TS cells. ELF3 overexpression in MDA-MB-231 and MCF7 cells caused reversal of TRAIL resistance as observed using cell viability assay and cleaved caspase-3 immunoblotting. ELF3 overexpression also resulted in DCR2 downregulation in the MDA-MB-231 and MCF7 cells. Furthermore, KM analysis found high ELF3 and low DCR2 expression to show better patient survival in the presence of TRAIL. CONCLUSION: Our study shows ELF3 to be an important factor that can influence TRAIL-mediated apoptosis in breast cancer. Also, ELF3 and DCR2 expression status should be taken into consideration while designing strategies for successful TRAIL-based therapy.


Subject(s)
Apoptosis , Breast Neoplasms , DNA-Binding Proteins , Drug Resistance, Neoplasm , Gene Expression Regulation, Neoplastic , TNF-Related Apoptosis-Inducing Ligand , Transcription Factors , Humans , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Cell Line, Tumor , Apoptosis/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/metabolism , Drug Resistance, Neoplasm/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , MCF-7 Cells , Tumor Necrosis Factor Decoy Receptors/genetics , Tumor Necrosis Factor Decoy Receptors/metabolism , Cell Survival/genetics , Cell Survival/drug effects , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , Proto-Oncogene Proteins c-ets
2.
Cancer Lett ; 525: 67-75, 2022 01 28.
Article in English | MEDLINE | ID: mdl-34728311

ABSTRACT

Genotoxic agents are widely used anti-cancer therapies because of their ability to interfere with highly proliferative cells. An important outcome of these interventions is the induction of a state of permanent arrest also known as cellular senescence. However, senescent cancer cells are characterized by genomic instability and are at risk of escaping the growth arrest to eventually facilitate cancer relapse. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) signals extrinsic apoptosis via Death Receptors (DR) 4 and 5, while Decoy Receptors (DcR) 1 and 2, and Osteoprotegerin (OPG) are homologous to death receptors but incapable of transducing an apoptotic signal. The use of recombinant TRAIL as an anti-cancer strategy in combination with chemotherapy is currently in development, and a major question remains whether senescent cancer cells respond to TRAIL. Here, we show variable sensitivity of cancer cells to TRAIL after senescence induction, and upregulation of both pro-apoptotic and anti-apoptotic receptors in therapy-induced senescent cancer cells. A DR5-selective TRAIL variant (DHER), unable to bind to DcR1 or OPG, was more effective in inducing apoptosis of senescent cancer cells compared to wild-type TRAIL. Importantly, no apoptosis induction was observed in non-cancerous cells, even at the highest concentrations tested. Our results suggest that targeting DR5 can serve as a novel therapeutic strategy for the elimination of therapy-induced senescent cancer cells.


Subject(s)
Breast Neoplasms/drug therapy , Osteoprotegerin/genetics , Ovarian Neoplasms/drug therapy , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/genetics , Apoptosis/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cellular Senescence/drug effects , Cellular Senescence/genetics , Doxorubicin/pharmacology , Female , GPI-Linked Proteins/genetics , Gene Expression Regulation, Neoplastic/drug effects , Genomic Instability/drug effects , Humans , MCF-7 Cells , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Signal Transduction/drug effects , Tumor Necrosis Factor Decoy Receptors/genetics
3.
J Mol Endocrinol ; 66(4): 325-338, 2021 05 11.
Article in English | MEDLINE | ID: mdl-33875613

ABSTRACT

Strategies to increase functional pancreatic beta cell mass is of great interest in diabetes-related research. TNF-related apoptosis-inducing ligand (TRAIL) is well known to promote proliferation and survival in various cell types, including vascular smooth muscle and endothelial cells. Correlation between the protective nature of TRAIL on these cells and its proliferative effect is noteworthy. TRAIL's seemingly protective/therapeutic effect in diabetes prompted us to question whether it may act as an inducer of proliferation in pancreatic beta cells. We used rat primary islet cells and MIN6 mouse beta cell line to investigate TRAIL-induced proliferation. Cell viability and/or death was analyzed by MTT, WST-1, and Annexin-V/PI assays, while proliferation rates and pathways were assessed via immunocytochemical and Western blot analyses. Receptor neutralization antibodies identified the mediator receptors. Recombinant soluble TRAIL (sTRAIL) treatment led to 1.6-fold increased proliferation in insulin-positive cells in dispersed rat islets compared to the untreated group, while adenovirus-mediated overexpression of TRAIL increased the number of proliferating beta cells up to more than six-fold. sTRAIL or adenoviral vector-mediated TRAIL overexpression induced proliferation in MIN6 cells also. TRAIL's proliferative effect was mediated via AKT activation, which was suppressed upon specific inhibition. Neutralization of each TRAIL receptor reversed the proliferative effect to some degree, with the highest level of inhibition in death receptor 5 (DR5) blockage in MIN6 cells and in decoy receptor 1 (DcR1) blockage in primary rat beta cells. Thus, TRAIL induces proliferation in rodent pancreatic beta cells through activation of the AKT pathway.


Subject(s)
Diabetes Mellitus/genetics , Insulin-Secreting Cells/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, Tumor Necrosis Factor, Member 10c/genetics , TNF-Related Apoptosis-Inducing Ligand/genetics , Animals , Apoptosis/genetics , Cell Proliferation/genetics , Cell Survival/genetics , Diabetes Mellitus/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Gene Expression Regulation/genetics , Humans , Insulin-Secreting Cells/pathology , Mice , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Proto-Oncogene Proteins c-akt/genetics , Rats
4.
BMC Cancer ; 21(1): 76, 2021 Jan 18.
Article in English | MEDLINE | ID: mdl-33461524

ABSTRACT

BACKGROUND: Breast cancer is the most frequently diagnosed malignancy among women. However, the role of microRNA (miRNA) expression in breast cancer progression is not fully understood. In this study we examined predictive interactions between differentially expressed miRNAs and mRNAs in breast cancer cell lines representative of the common molecular subtypes. Integrative bioinformatics analysis identified miR-193 and miR-210 as potential regulatory biomarkers of mRNA in breast cancer. Several recent studies have investigated these miRNAs in a broad range of tumors, but the mechanism of their involvement in cancer progression has not previously been investigated. METHODS: The miRNA-mRNA interactions in breast cancer cell lines were identified by parallel expression analysis and miRNA target prediction programs. The expression profiles of mRNA and miRNAs from luminal (MCF-7, MCF-7/AZ and T47D), HER2 (BT20 and SK-BR3) and triple negative subtypes (Hs578T e MDA-MB-231) could be clearly separated by unsupervised analysis using HB4A cell line as a control. Breast cancer miRNA data from TCGA patients were grouped according to molecular subtypes and then used to validate these findings. Expression of miR-193 and miR-210 was investigated by miRNA transient silencing assays using the MCF7, BT20 and MDA-MB-231 cell lines. Functional studies included, xCELLigence system, ApoTox-Glo triplex assay, flow cytometry and transwell inserts were performed to determine cell proliferation, cytotoxicity, apoptosis, migration and invasion, respectively. RESULTS: The most evident effects were associated with cell proliferation after miR-210 silencing in triple negative subtype cell line MDA-MB-231. Using in silico prediction algorithms, TNFRSF10 was identified as one of the potential regulated downstream targets for both miRNAs. The TNFRSF10C and TNFRSF10D mRNA expression inversely correlated with the expression levels of miR-193 and miR210 in breast cell lines and breast cancer patients, respectively. Other potential regulated genes whose expression also inversely correlated with both miRNAs were CCND1, a known mediator on invasion and metastasis, and the tumor suppressor gene RUNX3. CONCLUSIONS: In summary, our findings identify miR-193 and miR-210 as potential regulatory miRNA in different molecular subtypes of breast cancer and suggest that miR-210 may have a specific role in MDA-MB-231 proliferation. Our results highlight important new downstream regulated targets that may serve as promising therapeutic pathways for aggressive breast cancers.


Subject(s)
Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Gene Expression Regulation, Neoplastic/genetics , MicroRNAs/metabolism , Biomarkers, Tumor/analysis , Breast/pathology , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Computational Biology , Core Binding Factor Alpha 3 Subunit/genetics , Cyclin D1/genetics , Female , GPI-Linked Proteins/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , MicroRNAs/analysis , MicroRNAs/antagonists & inhibitors , MicroRNAs/genetics , Oligonucleotide Array Sequence Analysis , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Tumor Necrosis Factor Decoy Receptors/genetics
5.
Pathology ; 52(3): 348-358, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32111400

ABSTRACT

Deregulation of the receptors of TNF-related apoptosis inducing ligand (TRAIL) has been reported in various cancers. In an effort to define the role of these receptors we profiled their expression in gallbladder cancer (GBC) and explored their clinical significance. Expression of TRAIL receptors' mRNA in GBC was analysed through reverse transcriptase polymerase chain reaction (RT-PCR), and protein through western blotting, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). mRNA data show frequent higher expression of TRAIL receptors in GBC samples. Death receptors DR4 and DR5 showed significant negative correlation with tumour stage, T stage and tumour grade; DcR1 transcript showed positive correlation with tumour stage, N stage, M stage and tumour grade. Similarly, IHC showed frequent positive staining for DR4, DR5 and DcR1in GBC samples. Cytoplasmic and nuclear DR4 protein showed negative correlation with T stage and tumour grade, whereas cytoplasmic DcR1 protein showed positive correlation with tumour stage and N stage. Nuclear DcR1 showed positive correlation with N stage. ELISA results showed significantly higher expression of secretory DcR1 in GBC patients. Kaplan-Meier analysis demonstrated significantly decreased mean survival of patients with positive staining of cytoplasmic DcR1. High level of death receptors identified the patients with early gallbladder cancer, whereas high DcR1 expression served as a prognostic factor for poor outcome.


Subject(s)
Biomarkers, Tumor/analysis , Gallbladder Neoplasms/pathology , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , Adult , Aged , Female , GPI-Linked Proteins/analysis , GPI-Linked Proteins/metabolism , Humans , Male , Middle Aged , Prognosis , Receptors, TNF-Related Apoptosis-Inducing Ligand/analysis , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/analysis
6.
Nat Prod Res ; 34(12): 1735-1742, 2020 Jun.
Article in English | MEDLINE | ID: mdl-30580626

ABSTRACT

Novel Mannich base derivatives of glabridin were synthesized and their antiproliferative activity were performed along with our previously reported glabridin-chalcone hybrids molecules (GCHMs) against various human cell lines MDA-MB-231 (breast adenocarcinoma), HEK-293 (embryonic kidney cell line), K562 (leukemia), MCF-7 (breast adenocarcinoma), HeLa (cervix adenocarcinoma), HepG2 (hepatocellular carcinoma) and WRL-68 (hepatic carcinoma). The result showed that the glabridin significantly reduced cell proliferation with IC50 ranges from 3.67 to 58.30 µM against all the tested cell lines. The remarkable reduction in antiproliferative activity 2',4'-dimethoxyglabridin and GCHMs compounds with phenolic OH groups protected by methoxy (OCH3) groups suggested that the free OH groups are essential factor for the antiproliferative activity of glabridin and its derivatives. The Mannich base derivatives of glabridin showed moderate activity IC50 (2.20->95.78 µM). Furthermore, in silico target identification analysis revealed that AKT1, DECR1 and NOS1 are the potential targets for glabridin and their derivatives.


Subject(s)
Antineoplastic Agents/pharmacology , Isoflavones/pharmacology , Phenols/pharmacology , Antineoplastic Agents/chemistry , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Chalcone/pharmacology , Computer Simulation , GPI-Linked Proteins/antagonists & inhibitors , Humans , Isoflavones/chemical synthesis , Nitric Oxide Synthase Type I/antagonists & inhibitors , Phenols/chemical synthesis , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Receptors, Tumor Necrosis Factor, Member 10c/antagonists & inhibitors , Structure-Activity Relationship
7.
Am J Otolaryngol ; 40(6): 102258, 2019.
Article in English | MEDLINE | ID: mdl-31399243

ABSTRACT

OBJECTIVE: Tongue squamous cell carcinoma (TSCC) is one of the most common malignancies in the oral cavity, and its incidence and mortality have been constantly increasing these years. A large number of tumor suppressor genes are involved in the development of the TSCC and it has been reported that the aberrant hypermethylation of tumor suppressor genes may play a key role in the process of the TSCC. In this study, we sought to analyze the association of methylation of DcR1, DcR2, DR4 and DR5 gene promoters and clinical significance in the TSCC to evaluate association between methylation of DcR1, DcR2, DR4 and DR5 gene and Clinical Significance in tongue squamous cell carcinoma. METHODS: Methylation-specific PCR(MSP) was used to analyze the methylation of the promoters of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) receptors in 45 TSCC cases. Real-Time PCR was used to detect the expression of the DcR1, DcR2, DR4 and DR5 gene. RESULTS: All the four genes (DcR1, DcR2, DR4 and DR5) showed different methylation of promoters in TSCC, while methylation of these promoters in paired adjacent normal tissues were almost undetectable. Patients with high methylation index were diagnosed at younger age when compared with the ones with low methylation index. DcR1 and DR4 hypermethylation was correlated significantly with patients' TNM stage. CONCLUSIONS: Methylation of DcR1, DcR2,DR4 and DR5 promoters are found in TSCC and may associate with its occurrence and development. Taking the reversibility of methylation into account,methylation is a potential targeted therapy of TSCC.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , Tongue Neoplasms/metabolism , Tumor Necrosis Factor Decoy Receptors/metabolism , Adult , Biomarkers/metabolism , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Female , GPI-Linked Proteins/metabolism , Humans , Male , Methylation , Middle Aged , Neoplasm Staging , Promoter Regions, Genetic , Tongue Neoplasms/genetics , Tongue Neoplasms/pathology
8.
Transl Psychiatry ; 7(8): e1222, 2017 08 29.
Article in English | MEDLINE | ID: mdl-28850112

ABSTRACT

Chronic inflammation is a characteristic of post-traumatic stress disorder (PTSD). The initiation of inflammation and molecules involved are not yet clearly understood. Here, we provide compelling evidence that the inflammation seen in PTSD may result from the dysregulated miRNA processing pathway. Using microarray analysis with a discovery group of peripheral blood mononuclear cell (PBMC) samples from War Veterans with PTSD, we found 183 significantly downregulated miRNAs, several of which target numerous genes categorized to be pro-inflammatory in nature. This observation was further confirmed in a replicate group by including more samples. Furthermore, employing RNA-sequencing, quantitative real time PCR (qRT-PCR) and in vitro experiments, we found that Argonaute 2 (AGO2) and Dicer1 (DCR1) were downregulated in PTSD and provided convincing evidence that their downregulation affects mature miRNA generation. In addition, we noted that STAT3 transcript was reduced in PTSD and this was possibly responsible for reduced AGO2 and DCR1, which in turn affected miRNA synthesis. Furthermore, we observed that activation of CD4+ T cells or monocytes led to reduced mature miRNA availability. Finally, the inflammation seen in PTSD was associated with downregulated miRNA profile. Altogether, the current study demonstrates that the chronic inflammation seen in PTSD may be a result of dysregulated miRNA biogenesis pathway due to diminished expression of the key molecules like AGO2, DCR1 and STAT3.


Subject(s)
Argonaute Proteins/metabolism , Inflammation/metabolism , Leukocytes, Mononuclear/metabolism , MicroRNAs/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , Stress Disorders, Post-Traumatic/metabolism , Afghan Campaign 2001- , Down-Regulation , GPI-Linked Proteins/metabolism , Gulf War , Humans , Inflammation/complications , Iraq War, 2003-2011 , STAT3 Transcription Factor/metabolism , Stress Disorders, Post-Traumatic/complications , Veterans
9.
Sci Rep ; 7(1): 5514, 2017 07 17.
Article in English | MEDLINE | ID: mdl-28717244

ABSTRACT

The TRAIL pathway can mediate apoptosis of hepatic stellate cells to promote the resolution of liver fibrosis. However, TRAIL has the capacity to bind to regulatory receptors in addition to death-inducing receptors; their differential roles in liver fibrosis have not been investigated. Here we have dissected the contribution of regulatory TRAIL receptors to apoptosis resistance in primary human hepatic stellate cells (hHSC). hHSC isolated from healthy margins of liver resections from different donors expressed variable levels of TRAIL-R2/3/4 (but negligible TRAIL-R1) ex vivo and after activation. The apoptotic potential of TRAIL-R2 on hHSC was confirmed by lentiviral-mediated knockdown. A functional inhibitory role for TRAIL-R3/4 was revealed by shRNA knockdown and mAb blockade, showing that these regulatory receptors limit apoptosis of hHSC in response to both oligomerised TRAIL and NK cells. A close inverse ex vivo correlation between hHSC TRAIL-R4 expression and susceptibility to apoptosis underscored its central regulatory role. Our data provide the first demonstration of non-redundant functional roles for the regulatory TRAIL receptors (TRAIL-R3/4) in a physiological setting. The potential for these inhibitory TRAIL receptors to protect hHSC from apoptosis opens new avenues for prognostic and therapeutic approaches to the management of liver fibrosis.


Subject(s)
Apoptosis , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Antibodies, Monoclonal/immunology , Apoptosis/drug effects , Cells, Cultured , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Hepatic Stellate Cells/cytology , Hepatic Stellate Cells/metabolism , Humans , Killer Cells, Natural/immunology , Liver/cytology , RNA Interference , RNA, Small Interfering/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitors , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology , Receptors, Tumor Necrosis Factor, Member 10c/antagonists & inhibitors , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Tumor Necrosis Factor Decoy Receptors/antagonists & inhibitors , Tumor Necrosis Factor Decoy Receptors/genetics , Tumor Necrosis Factor Decoy Receptors/metabolism
10.
BMC Cancer ; 17(1): 280, 2017 04 18.
Article in English | MEDLINE | ID: mdl-28420351

ABSTRACT

BACKGROUND: Tumor epithelial cells (TEpCs) and spindle-shaped stromal cells, not associated with the vasculature, of patients with early breast cancer express osteoprotegerin (OPG), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), receptor activator of nuclear factor kappa B ligand, stromal cell derived factor-1, interleukin-6, macrophage colony stimulating factor, chemokine (C-C motif) ligand-2 (CCL-2) and their receptors at significantly higher levels compared with non-neoplastic breast tissues. We evaluated the clinicopathological significance of these ligands and receptors in TEpC and spindle-shaped stromal cells, not associated with the vasculature, to determine their impact on prognosis of patients with early-stage breast cancer. METHODS: We conducted immunohistochemical analyses of protein expression in primary tumors of patients with early breast cancer and analyzed their association with standard prognostic parameters and clinical outcomes, including local relapse, metastatic recurrence, disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). RESULTS: Elevated levels of TRAIL-R3 and chemokine (C-C motif) receptor 2 (CCR-2) in TEpCs and OPG and CCL-2 in stromal cells were significantly associated with a higher risk of metastasis (p = 0.032, p = 0.003, p = 0.038, and p = 0.049; respectively). Moreover, high expression of TRAIL-R3 and CCR-2 in TEpCs was associated with shorter DFS, MFS, and OS. High TRAIL-R3 expression in TEpCs was an independent prognostic factor for DFS and OS, and high CCR-2 expression in these cells was an independent prognostic factor for MFS. CONCLUSIONS: High levels of TRAIL-R3 and CCR-2 expression in TEpCs identified patients with early breast cancer with poor outcomes.


Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/pathology , Epithelial Cells/metabolism , Receptors, CCR2/biosynthesis , Receptors, Tumor Necrosis Factor, Member 10c/biosynthesis , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Epithelial Cells/pathology , Female , GPI-Linked Proteins/analysis , GPI-Linked Proteins/biosynthesis , Humans , Immunohistochemistry , Middle Aged , Prognosis , Receptors, CCR2/analysis , Receptors, Tumor Necrosis Factor, Member 10c/analysis , Retrospective Studies
11.
Apoptosis ; 22(7): 920-932, 2017 07.
Article in English | MEDLINE | ID: mdl-28409399

ABSTRACT

Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.


Subject(s)
Apoptosis/drug effects , Breast Neoplasms/drug therapy , Interferon Regulatory Factor-3/genetics , TNF-Related Apoptosis-Inducing Ligand/genetics , Apoptosis/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Female , GPI-Linked Proteins/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Interferon Type I/genetics , RNA, Double-Stranded/administration & dosage , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Toll-Like Receptor 3/genetics , Tretinoin/administration & dosage
12.
Exp Gerontol ; 90: 83-89, 2017 04.
Article in English | MEDLINE | ID: mdl-28189700

ABSTRACT

OBJECTIVE: Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). METHODS: Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aß1-42 and total tau CSF analytes. RESULTS: The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p<0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10-5). Further, the rs5848 SNP status was associated with increased CSF tau protein - a marker of neurodegeneration (p=0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.


Subject(s)
Aging/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Dementia/genetics , Hippocampus/pathology , Intercellular Signaling Peptides and Proteins/genetics , Aged , Aged, 80 and over , Amyloid beta-Peptides/cerebrospinal fluid , Clusterin/cerebrospinal fluid , Databases, Factual , Dementia/cerebrospinal fluid , Female , GPI-Linked Proteins/cerebrospinal fluid , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide , Progranulins , Receptors, Tumor Necrosis Factor, Member 10c/cerebrospinal fluid , Regression Analysis , Risk Factors , Sclerosis , Vascular Cell Adhesion Molecule-1/cerebrospinal fluid , tau Proteins/cerebrospinal fluid
13.
Biomed Pharmacother ; 88: 349-358, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28119237

ABSTRACT

Betulinic acid (BA), isolated from the tree bark, is a pentacyclic triterpenoid, showing inhibitory role in cancer cells. However, the effects of BA treatment on liver cancer have little to be known. Thus, the study is conducted to explore the in vitro and in vivo role of BA in liver cancer. And the interactions between BA and tumor necrosis factor-related apoptosis-inducing ligand of APO2, also known as TRAIL, were investigated in liver cancer cells. A synergistic effect of BA and APO2 combination on apoptosis induction in liver cancer cells was observed. The cancer cells were insensitive to APO2 single therapy. However, liver cancer cells receiving BA were sensitive to APO2-triggered apoptotic response by enhancing Caspases cleavage, due to elevation of decoy receptor 1 and 2 (DcR1 and DcR2) dependent on p53. Bcl-2 family members of Bcl-2 and Mcl-1, belonging to anti-apoptosis, were decreased, whereas Bad and Bak, as pro-apoptotic members, were increased for BA and APO2 combined treatment. Additionally, the mouse xenograft model suggested that BA and APO2 in combination markedly inhibited liver cancer growth in comparison to BA or APO2 monotherapy without toxicity. The present study revealed a dramatically therapeutic strategy for promoting APO2-induced anti-cancer effects on liver cancer cells via BA combination.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Caspase 3/drug effects , Liver Neoplasms/drug therapy , Signal Transduction/drug effects , TNF-Related Apoptosis-Inducing Ligand/metabolism , Triterpenes/pharmacology , Tumor Suppressor Protein p53/drug effects , Animals , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Cell Line, Tumor , GPI-Linked Proteins/metabolism , Humans , Liver Neoplasms/pathology , Mice , Mice, Nude , Pentacyclic Triterpenes , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , TNF-Related Apoptosis-Inducing Ligand/drug effects , Tumor Necrosis Factor Decoy Receptors/metabolism , Tumor Necrosis Factor-alpha/metabolism , Tumor Stem Cell Assay , Xenograft Model Antitumor Assays , Betulinic Acid
14.
Neoplasma ; 64(2): 182-191, 2017.
Article in English | MEDLINE | ID: mdl-28043144

ABSTRACT

The activation of AKT is one of the causes of resistance to epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitors (TKIs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combines with related receptors to trigger apoptosis or protect the cells against TRAIL apoptosis. This research focused on the association of EGFR and KRAS mutations with expression of AKT, p-AKT, DR5 and DcR1 in non-small cell lung cancer. 82 NSCLC patients were included in the study. xTAG liquichip techonolgy (xTAG-LCT) was applied to investigate the genetic mutation of EGFR and KRAS, Quantitative Real-time PCR was used to test the mRNA expression of AKT, DR5 and DcR1 and Western Blot was applied to test the protein expression of AKT, p-AKT, DR5, and DcR1. We found that of 82 patients, 31 cases had EGFR-activating mutations, more common in female, adenocarcinoma, and non-smoker patients; 9 cases had KRAS mutations, frequently found in patients with smoking history. The expression of AKT and p-AKT correlated with staging, tumor differentiation, and lymph node metastasis. The expression of DR5 in phase III and low differentiation tumor was significantly higher than that in phase I+II and high and median differentiation tumor; the expression of DcR1 in phase III and low differentiation tumor was significantly lower than that in phase I+II and high and median differentiation tumor. Compared with EGFR and KRAS wild type, in NSCLC tissue with EGFR and KRAS mutations, the expression of AKT and p-AKT was significantly higher. These results suggest that EGFR and KRAS mutation status was associated with the expression of AKT and p-AKT. AKT, p-AKT, DR5, and DcR1 all took part in the occurrence and development of NSCLC, and may become a reference index to evaluate the prognosis of NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , ErbB Receptors/genetics , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Humans , Male , Mutation , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Receptors, Tumor Necrosis Factor, Member 10c/metabolism
15.
Pancreas ; 45(3): 401-8, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26390425

ABSTRACT

OBJECTIVES: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is currently being evaluated as a possible biological agent for cancer treatment. However, many tumor cells are resistant to TRAIL-induced apoptosis. In these cases, TRAIL may activate different pathways promoting tumor growth as well as showing different interactions with the immunological tumor microenvironment. In this study, the impact of TRAIL on tumor growth and survival in a syngeneic model of TRAIL-resistant pancreatic cancer cells was investigated. METHODS: Murine 6606PDA pancreatic cancer cells were injected into the pancreatic heads of TRAIL mice and their littermates. To examine a direct effect of TRAIL on tumor cells, cultures of 6606PDA were TRAIL stimulated. RESULTS: The TRAIL mice displayed significantly decreased tumor volumes and an enhanced overall survival in pancreatic cancer. The decreased tumor growth in TRAIL mice was accompanied by a decrease of regulatory CD4 cells within tumors. Concordantly, TRAIL treatment of wild-type mice enhanced tumor growth and increased the fraction of regulatory CD4 cells. Yet, a direct effect of TRAIL on 6606PDA cells was not detected. CONCLUSIONS: Thus, TRAIL can promote tumor growth in TRAIL-resistant tumor cells. This may restrict possible future clinical applications of TRAIL in pancreatic cancer.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Pancreatic Neoplasms/drug therapy , T-Lymphocytes, Regulatory/drug effects , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Animals , Blotting, Western , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/immunology , Humans , Kaplan-Meier Estimate , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/metabolism , Transplantation, Isogeneic , Tumor Burden/drug effects , Tumor Burden/genetics , Tumor Burden/immunology , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
16.
Genes Chromosomes Cancer ; 55(2): 177-89, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26542757

ABSTRACT

Multiple chromosomal regions are affected by deletions in cervical cancer (CC) genomes, but their consequence and target gene involvement remains unknown. Our single nucleotide polymorphism (SNP) array identified 8p copy number losses localized to an 8.4 Mb minimal deleted region (MDR) in 36% of CC. The 8p MDR was associated with tumor size, treatment outcome, and with multiple HPV infections. Genetic, epigenetic, and expression analyses of candidate genes at MDR identified promoter hypermethylation and/or inactivation of decoy receptors TNFRSF10C and TNFRSF10D in the majority of CC patients. TNFRSF10C methylation was also detected in precancerous lesions suggesting that this change is an early event in cervical tumorigenesis. We further demonstrate here that CC cell lines exhibiting downregulated expression of TNFRSF10C and/or TNFRSF10D effectively respond to TRAIL-induced apoptosis and this affect was synergistic in combination with DNA damaging chemotherapeutic drugs. We show that the CC cell lines harboring epigenetic inactivation of TRAIL decoy receptors effectively activate downstream caspases suggesting a critical role of inactivation of these genes in efficient execution of extrinsic apoptotic pathway and therapy response. Therefore, these findings shed new light on the role of genetic/epigenetic defects in TRAIL decoy receptor genes in the pathogenesis of CC and provide an opportunity to explore strategies to test decoy receptor gene inactivation as a biomarker of response to Apo2L/TRAIL-combination therapy.


Subject(s)
Cisplatin/pharmacology , DNA Methylation , Receptors, Tumor Necrosis Factor, Member 10c/genetics , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Tumor Necrosis Factor Decoy Receptors/genetics , Uterine Cervical Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols , Base Sequence , Cell Line, Tumor , Cell Survival/drug effects , Chromosomes, Human, Pair 8/genetics , Cisplatin/therapeutic use , Epigenesis, Genetic , Female , GPI-Linked Proteins/genetics , HeLa Cells , Humans , Middle Aged , Polymorphism, Single Nucleotide , Sequence Deletion , Uterine Cervical Neoplasms/genetics
17.
Oncogene ; 35(10): 1261-70, 2016 Mar 10.
Article in English | MEDLINE | ID: mdl-26050621

ABSTRACT

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand cytokine known for its cytotoxic activity against malignantly transformed cells. TRAIL induces cell death through binding to death receptors DR4 and DR5. The inhibitory decoy receptors (DcR1 and DcR2) co-expressed with death receptor 4 (DR4)/DR5 on the same cell can block the transmission of the apoptotic signal. Here, we show that DcRs also regulate TRAIL sensitivity at a supracellular level and thus represent a mechanism by which the microenvironment can diminish tumour TRAIL sensitivity. Mathematical modelling and layered or spheroid stroma-extracellular matrix-tumour cultures were used to model the tumour microenvironment. By engineering TRAIL to escape binding by DcRs, we found that DcRs do not only act in a cell-autonomous or cis-regulatory manner, but also exert trans-cellular regulation originating from stromal cells and affect tumour cells, highlighting the potent inhibitory effect of DcRs in the tumour tissue and the necessity of selective targeting of the two death-inducing TRAIL receptors to maximise efficacy.


Subject(s)
Receptors, Tumor Necrosis Factor, Member 10c/metabolism , Stromal Cells/pathology , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Necrosis Factor Decoy Receptors/metabolism , Cell Line, Tumor , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Humans , Models, Biological , Models, Molecular , Mutagenesis, Site-Directed , Mutation , Protein Conformation , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Stromal Cells/metabolism , TNF-Related Apoptosis-Inducing Ligand/chemistry , TNF-Related Apoptosis-Inducing Ligand/genetics , Tumor Necrosis Factor Decoy Receptors/genetics
18.
Asian Pac J Cancer Prev ; 16(16): 6991-6, 2015.
Article in English | MEDLINE | ID: mdl-26514480

ABSTRACT

In the past decade, the incidence and mortality rates of cholangiocarcinoma (CCA) have been increasing worldwide. The relatively low responsiveness of CCA to conventional chemotherapy leads to poor overall survival. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) has emerged as the most promising anti-cancer therapeutic agent since it is able to selectively induce apoptosis of tumor cells but not normal cells. In this study, we aimed to investigate the therapeutic effect of TRAIL in CCA cell lines (M213, M214 and KKU100) compared with the immortal biliary cell line, MMNK1, either alone or in combination with a subtoxic dose of 5-fluorouracil (5-FU). We found that recombinant human TRAIL (rhTRAIL) was a potential agent which significantly inhibited cell proliferation and mediated caspase activities (caspases 8, 9 and 3/7) and apoptosis of CCA cells. The combined treatment of rhTRAIL and 5-FU effectively enhanced inhibition of CCA cell growth with a smaller effect on MMNK1. Our finding suggests TRAIL to be a novel anti-cancer therapeutic agent and advantage of its combination with a conventional chemotherapeutic drug for effective treatment of CCA.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bile Duct Neoplasms/drug therapy , Cholangiocarcinoma/drug therapy , Fluorouracil/pharmacology , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Apoptosis/drug effects , Caspases/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Fluorouracil/administration & dosage , GPI-Linked Proteins/genetics , Gene Expression/drug effects , Humans , RNA, Messenger/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/genetics , TNF-Related Apoptosis-Inducing Ligand/administration & dosage , Tumor Necrosis Factor Decoy Receptors/genetics , Tumor Suppressor Protein p53/genetics
19.
Clin Cancer Res ; 21(23): 5338-48, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26152738

ABSTRACT

PURPOSE: Preclinical studies show that inhibition of aurora kinases in melanoma tumors induces senescence and reduces tumor growth, but does not cause tumor regression. Additional preclinical models are needed to identify agents that will synergize with aurora kinase inhibitors to induce tumor regression. EXPERIMENTAL DESIGN: We combined treatment with an aurora kinase A inhibitor, MLN8237, with agents that activate death receptors (Apo2L/TRAIL or death receptor 5 agonists) and monitored the ability of this treatment to induce tumor apoptosis and melanoma tumor regression using human cell lines and patient-derived xenograft (PDX) mouse models. RESULTS: We found that this combined treatment led to apoptosis and markedly reduced cell viability. Mechanistic analysis showed that the induction of tumor cell senescence in response to the AURKA inhibitor resulted in a decreased display of Apo2L/TRAIL decoy receptors and increased display of one Apo2L/TRAIL receptor (death receptor 5), resulting in enhanced response to death receptor ligand/agonists. When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status. Senescent tumor cells exhibited BID-mediated mitochondrial depolarization in response to Apo2L/TRAIL treatment. In addition, senescent tumor cells had a lower apoptotic threshold due to decreased XIAP and survivin expression. Melanoma tumor xenografts of one human cell line and one PDX displayed total blockage of tumor growth when treated with MLN8237 combined with DR5 agonist antibody. CONCLUSIONS: These findings provide a strong rationale for combining senescence-inducing therapeutics with death receptor agonists for improved cancer treatment.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Aurora Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Receptors, Death Domain/agonists , Animals , Apoptosis/genetics , Azepines/pharmacology , Caspases/metabolism , Cell Line, Tumor , Cellular Senescence/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/metabolism , Melanoma/pathology , Mice , Pyrimidines/pharmacology , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , Signal Transduction/drug effects , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays
20.
Cell Physiol Biochem ; 36(3): 1151-62, 2015.
Article in English | MEDLINE | ID: mdl-26111475

ABSTRACT

BACKGROUND/AIMS: Although Vitisin A, derived from wine grapes, is known to have cytotoxic, anti-adipogenic, anti-inflammatory and antioxidant effects, the underlying antitumor mechanism has not been investigated in prostate cancer cells to date. In the present study, the apoptotic mechanism of Vitisin A plus TNF-related apoptosis-inducing ligand (TRAIL) in prostate cancer cells was elucidated. METHODS: The cytotoxicity of Vitisin A and/or TRAIL against PC-3, DU145 and LNCaP prostate cancer cells was measured by MTT colorimetric assay. Annexin V-FITC Apoptosis Detection kit was used to detect apoptotic cells by flow cytometry. Intracellular levels of ROS were measured by flow cytometry using 2070-diacetyl dichlorofluorescein (DCFDA). RESULTS: Combined treatment with Vitisin A and TRAIL enhanced cytotoxicity and also increased sub-G1 population in PC-3 cells better than DU145 or LNCap prostate cancer cells. Similarly, Annexin V and PI staining revealed that combination increased early and late apoptosis in PC-3 cells compared to untreated control. Consistently, combination attenuated the expression of pro-caspases 7/8, DcR1, Bcl-XL or Bcl-2 and activated caspase 3, FADD, DR5 and DR4 in PC-3 cells. Also, combination increased DR5 promoter activity compared to untreated control. Furthermore, combination increased the production of reactive oxygen species (ROS) and DR5 cell surface expression. The ROS inhibitor NAC and silencing of DR5 by siRNA transfection inhibited the ability of combination to induce PARP cleavage and generate ROS. CONCLUSION: These findings provide evidence that Vitisin A can be used in conjunction with TRAIL as a potent TRAIL sensitizer for synergistic apoptosis induction via upregulation of DR5 and production of ROS in prostate cancer cells.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Benzofurans/pharmacology , Gene Expression Regulation, Neoplastic , Phenols/pharmacology , Prostate/drug effects , Reactive Oxygen Species/agonists , Receptors, TNF-Related Apoptosis-Inducing Ligand/agonists , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Apoptosis/drug effects , Caspase 7/genetics , Caspase 7/metabolism , Caspase 8/genetics , Caspase 8/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Drug Combinations , Drug Synergism , Fas-Associated Death Domain Protein/genetics , Fas-Associated Death Domain Protein/metabolism , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Humans , Male , Prostate/metabolism , Prostate/pathology , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Reactive Oxygen Species/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/antagonists & inhibitors , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Receptors, Tumor Necrosis Factor, Member 10c/genetics , Receptors, Tumor Necrosis Factor, Member 10c/metabolism , Signal Transduction , bcl-X Protein/genetics , bcl-X Protein/metabolism
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