TNFRSF10A

Gene Summary

Gene:TNFRSF10A; TNF receptor superfamily member 10a
Aliases: DR4, APO2, CD261, TRAILR1, TRAILR-1
Location:8p21.3
Summary:The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL), and thus transduces cell death signal and induces cell apoptosis. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor receptor superfamily member 10A
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TNFRSF10A (cancer-related)

Park JS, Lim CJ, Bang OS, Kim NS
Ethanolic extract of Descurainia sophia seeds sensitizes A549 human lung cancer cells to TRAIL cytotoxicity by upregulating death receptors.
BMC Complement Altern Med. 2016; 16:115 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Our previous genome-wide gene expression analysis revealed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors 4 (DR4) and 5 (DR5) are markedly upregulated by the ethanolic extract of D. sohia seeds (EEDS) in A549 TRAIL-refractory cancer cells. In the present study, we investigated whether the EEDS-mediated upregulation of TRAIL death receptors was associated with increased TRAIL-mediated toxicity in A549 cells in vitro.
METHODS: Cell proliferation and viability were determined by an automatic cell counter. Gene silencing was performed by introducing small interfering RNA into cells. Expression changes of cellular proteins were determined by western blot analysis. Apoptotic cell death was monitored by western blot analysis. Analysis of variance followed by the post-hoc Dunnett's test was used to compare the data.
RESULTS: EEDS treatment increased both mRNA and protein levels of DR4 and DR5 in the TRAIL refractory A549 cells. Co-treatment of A549 cells with sub-lethal dose of EEDS and recombinant TRAIL increased the apoptotic cell death. Upregulation of DR5 by EEDS was mediated by an endoplasmic reticulum stress-induced transcription factor, CCAAT/enhancer-binding protein homologous protein (CHOP), and knockdown of CHOP expression inhibited EEDS-induced DR5 upregulation and abolished the EEDS-associated increase in TRAIL toxicity in A549 cells.
CONCLUSIONS: EEDS can sensitize A549 cells to TRAIL cytotoxicity by upregulation of TRAIL death receptors. Our findings suggested that EEDS is a good initial herbal source for the development of an anticancer supplement for anticancer therapeutics associated with TRAIL.

Bao YX, Zhao XD, Deng HB, et al.
Schedule-dependent cytotoxicity of sunitinib and TRAIL in human non-small cell lung cancer cells with or without EGFR and KRAS mutations.
Cell Oncol (Dordr). 2016; 39(4):343-52 [PubMed] Related Publications

De Miguel D, Gallego-Lleyda A, Ayuso JM, et al.
TRAIL-coated lipid-nanoparticles overcome resistance to soluble recombinant TRAIL in non-small cell lung cancer cells.
Nanotechnology. 2016; 27(18):185101 [PubMed] Related Publications
PURPOSE: Non-small cell lung cancer (NSCLC) is one the types of cancer with higher prevalence and mortality. Apo2-Ligand/TRAIL is a TNF family member able to induce apoptosis in tumor cells but not in normal cells. It has been tested in clinical trials against different types of human cancer including NSCLC. However, results of clinical trials have shown a limited efficacy of TRAIL-based therapies. Recently we have demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) greatly improved TRAIL cytotoxic ability being capable of killing chemoresistant hematological cancer cells. In the present work we have extended the study to NSCLC.
METHODS/PATIENTS: LUV-TRAIL-induced cytotoxicity was assessed on different NSCLC cell lines with different sensitivity to soluble TRAIL and on primary human tumor cells from three patients suffering from NSCLC cancer. We also tested LUV-TRAIL-cytotoxic ability in combination with several anti-tumor agents.
RESULTS: LUV-TRAIL exhibited a greater cytotoxic effect compared to soluble TRAIL both in A549 cells and primary human NSCLC cells. LUV-TRAIL-induced cell death was dependent on caspase-8 and caspase-3 activation. Moreover, combination of LUV-TRAIL with other anti-tumor agents such as flavopiridol, and SNS-032 clearly enhanced LUV-TRAIL-induced cytotoxicity against NSCLC cancer cells.
CONCLUSION: The novel formulation of TRAIL based on displaying it on the surface of lipid nanoparticles greatly increases its anti-tumor activity and has clinical potential in cancer treatment.

Kim EO, Kang SE, Im CR, et al.
Tanshinone IIA induces TRAIL sensitization of human lung cancer cells through selective ER stress induction.
Int J Oncol. 2016; 48(5):2205-12 [PubMed] Related Publications
Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promised anticancer medicine targeting only the tumor, most cancers show resistance to TRAIL-induced apoptosis. For this reason, new therapeutic strategies to overcome the TRAIL resistance are required for more effective tumor treatment. In the present study, potential of tanshinone IIA as a TRAIL sensitizer was evaluated in human non-small cell lung cancer (NSCLC) cells. NSCLC cells showed resistance to TRAIL-mediated cell death, but combination treatment of Tanshinone IIA and TRAIL synergistically decreased cell viability and increased apoptosis in TRAIL-resistant NSCLC cells. Tanshinone IIA greatly induced death receptor 5 (DR5), but not death receptor 4 (DR4). Furthermore, DR5 knockdown attenuated the combination treatment of tanshinone IIA with TRAIL-mediated cell death in human NSCLC cells. Tanshinone IIA also increased CHOP and activated the PERK-ATF4 pathway suggesting that tanshinone IIA increased DR5 and CHOP by activating the PERK-ATF4 pathway. Tanshinone IIA also downregulated phosphorylation of STAT3 and expression of survivin. Taken together, these results indicate that tanshinone IIA increases TRAIL-induced cell death via upregulating DR5 and downregulating survivin mediated by, respectively, selective activation of PERK/ATF4 and inhibition of STAT3, suggesting combinatorial intervention of tanshinone IIA and TRAIL as a new therapeutic strategy for human NSCLC.

Cousin FJ, Jouan-Lanhouet S, Théret N, et al.
The probiotic Propionibacterium freudenreichii as a new adjuvant for TRAIL-based therapy in colorectal cancer.
Oncotarget. 2016; 7(6):7161-78 [PubMed] Free Access to Full Article Related Publications
TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a well-known apoptosis inducer, which activates the extrinsic death pathway. TRAIL is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by cell resistance to cell death which occurs in approximately 50% of cancer cells. Short Chain Fatty Acids (SCFA) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate and acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. Indeed, we hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, increased pro-apoptotic gene expression (TRAIL-R2/DR5) and decreased anti-apoptotic gene expression (FLIP, XIAP) in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on both death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and caspases (caspase-8, -9 and -3) activation, was lethal on cancer cells but not on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented by P. freudenreichii induced HT29 cells apoptosis and enhanced TRAIL cytotoxic activity, as did P. freudenreichii DMEM culture supernatants or its SCFA metabolites. These results open new perspectives for food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer.

Saito Y, Nagae G, Motoi N, et al.
Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma.
Cancer Sci. 2016; 107(3):320-5 [PubMed] Free Access to Full Article Related Publications
Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome-wide methylation profile of SCLC. We investigated the genome-wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non-negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non-CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis-related chemotherapeutic agents for treatment of the aggressive tumor.

Brentville VA, Metheringham RL, Gunn B, et al.
Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell-Mediated Antitumor Immunity.
Cancer Res. 2016; 76(3):548-60 [PubMed] Related Publications
Stressful conditions in the harsh tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. However, autophagy also causes post-translational modification of proteins that are recognized by the immune system. In particular, modified self-antigens can trigger CD4(+) T-cell responses that might be exploited to boost antitumor immune defenses. In this study, we investigated the ability of CD4 cells to target tumor-specific self-antigens modified by citrullination, which converts arginine residues in proteins to citrulline. Focusing on the intermediate filament protein vimentin, which is frequently citrullinated in cells during epithelial-to-mesenchymal transition of metastasizing epithelial tumors, we generated citrullinated vimentin peptides for immunization experiments in mice. Immunization with these peptides induced IFNγ- and granzyme B-secreting CD4 T cells in response to autophagic tumor targets. Remarkably, a single immunization with modified peptide, up to 14 days after tumor implant, resulted in long-term survival in 60% to 90% of animals with no associated toxicity. This antitumor response was dependent on CD4 cells and not CD8(+) T cells. These results show how CD4 cells can mediate potent antitumor responses against modified self-epitopes presented on tumor cells, and they illustrate for the first time how the citrullinated peptides may offer especially attractive vaccine targets for cancer therapy.

Sarwar R, Mansoor Q, Farooqi AA, et al.
Genetic variants in the tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) do not contribute but Death Receptor (DR4) genes may contribute to susceptibility to head and neck cancer in Pakistani population.
Cell Mol Biol (Noisy-le-grand). 2015; 61(8):53-6 [PubMed] Related Publications
TRAIL mediated signaling in cancer cells has emerged as one amongst the most deeply studied molecular phenomenon. Recent breakthroughs have shown that overexpression of anti-apoptotic proteins, inactivation of pro-apoptotic proteins, transcriptional downregulation of TRAIL, DR4/DR5, degradation of DR/DR5 are some of the mechanisms which dramatically abrogate TRAIL induced apoptosis in cancer cells. Data obtained through genetic studies has highlighted highly polymorphic nature of DR4 and in accordance with this concept, we investigated the association between Head and Neck Cancer and polymorphisms in TRAIL (1595 C/T) and DR4 (C626G and A1322G) gene. We selected 100 patients with Head and Neck Cancer and 100 healthy, sex and age matched volunteers randomly. C626G and A1322G in DR4 gene were analyzed using Polymerase Change Reaction (PCR) - Restriction Fragment Length Polymorphism (RFLP) and Amplification Refractory Mutation System (ARMS) techniques respectively. For TRAIL gene 1595 C>T genotypes, there was no statistically significant role of homozygous CC or TT in Head and Neck cancer. CC was 58% in patients and 49% in controls. CT was 30% in patients and 43% in controls. TT was 12% in patients and 8% in controls. Allele frequency for C was noted to be 0.73 (patients) and 0.705 (controls), p-value (1). For T, 0.025 (patients) and 0.001(controls), p-value (0.88). The genotyping for DR4 gene 626 C>G polymorphism was done for 100 head and neck cancer patients and 100 age and sex matched healthy controls. All the genotypes for the polymorphism were in Hardy-Weinberg Equilibrium. For DR4626 C>G genotype, CC was 10% in patients and 2% in controls. GC was 63% in patients and 40% in controls. GG was 27% in patients and 58% in controls. Interestingly, in DR4 genotyping, CC was predisposing factor and GG acted as a protective factor. Allele frequency for C was noted to be 0.41 (patients) and 0.22 (controls), p-value (0.81). For G, 0.585 (patients) and 0.78 (controls), p-value (0.867). For the A1322G polymorphism, TT was 23% in patients and 36% in controls with a p-value 0.09 (table 6). CT was statistically significant in patients (45%) and controls (28%), p-value 0.04. CC was non-significant in patients (32%) and controls (36%), p-value 0.62 (table 6). C allele was 0.45% in patients and 0.5% in controls. T allele was 0.54% in patients and 0.5% in controls. Future studies must converge on somatic mutations, epigenetic mutations and expression analysis of TRAIL and DR4 to get a step closer to individualized medicine.

Zheng S, Chen H, Wang Y, et al.
Long non-coding RNA LOC389641 promotes progression of pancreatic ductal adenocarcinoma and increases cell invasion by regulating E-cadherin in a TNFRSF10A-related manner.
Cancer Lett. 2016; 371(2):354-65 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we found that a novel lncRNA, LOC389641, was upregulated in PDAC tissues and cell lines. The expression of LOC389641 was significantly correlated with staging, lymph node metastasis and overall survival. Knockdown of LOC389641 impaired cell proliferation and invasion and induced cell apoptosis in vitro, whereas overexpression of LOC389641 had the opposite effect. The growth promoting effect of LOC389641 was also demonstrated in vivo. Further, a significant negative correlation was observed between E-cadherin levels and LOC389641 levels in vivo. Knockdown of LOC389641 upregulated E-cadherin expression, but knockdown of E-cadherin had a limited influence on LOC389641. Importantly, after E-cadherin was inhibited, the enhancement of LOC389641 on cell invasion was hindered. Moreover, the expression of LOC389641 was closely associated with its genomic neighboring gene TNFRSF10A. Lastly, knockdown experiments showed that TNFRSF10A might be a connection between LOC389641and E-cadherin. We conclude that LOC389641 promotes PDAC progression and increases cell invasion by regulating E-cadherin with the possible involvement of TNFRSF10A.

Song Y, Peng X, Wang M, et al.
Gene expression profiling of taxol-resistant nasopharyngeal carcinoma cells with siRNA-mediated FOLR1 downregulation.
Int J Clin Exp Pathol. 2015; 8(9):11314-22 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: Our previous study has shown that downregulation of FOLR1 by siRNA partially reversed taxol-resistant phenotype in taxol-resistant nasopharyngeal carcinoma cell lines. We aim to gain further insight into the molecular mechanisms of this process and identify the differentially expressed genes after FOLR1 downregulation.
METHOD: The global gene expression profile was identified and analyzed using the Affymetrix HG-U133 Plus 2.0 array.
RESULTS: There was a significant dysregulation in the global gene expression of the FOLR1-suppressed taxol-resistant nasopharyngeal carcinoma cell lines. There were 41 upregulated genes and 109 downregulated genes. QRT-PCR validation of the selected differentially expressed genes demonstrated there was a good correlation with the microarray analysis. There was a significant deregulation of expression in the apoptosis-related genes such as BIRC3, PRKX, TNFRSF10A and involved in Viral carcinogenesis, MAPK signaling pathways after FOLR1 was downregulated.
CONCLUSION: The suppression of FOLR1 by RNA interference altered gene expression profile of taxol-resistant nasopharyngeal carcinoma cell lines. The apoptosis-related genes and the gene alterations in viral carcinogenesis, MAPK signaling pathways might be important in FOLR1 siRNA-induced taxol-resistant reversal.

Rai R, Kim JJ, Misra S, et al.
A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.
Int J Mol Sci. 2015; 16(12):28038-49 [PubMed] Free Access to Full Article Related Publications
Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p < 0.0001, CVC = 10/10) or in combination with DCC (rs714 and rs2229080, p < 0.0001, CVC = 9/10). Our CRT results are in agreement with the above findings. Further, in-silico results of studied SNPs advocated their role in splicing, transcriptional and/or protein coding regulation. Overall, our result suggested complex interactions amongst the studied SNPs and ADRB3 rs4994 as candidate influencing GBC susceptibility.

Park C, Jeong JS, Jeong JW, et al.
Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells.
Int J Oncol. 2016; 48(1):261-70 [PubMed] Related Publications
The Kalopanax septemlobus leaf (Thunb.) Koidz. has been used as a traditional medicine herb for the treatment of various human diseases for hundreds of years. In this study, we investigated the mechanism underlying the inhibitory effects of an ethanol extract of K. septemlobus leaf (EEKS) on proliferation of HepG2 hepatocellular carcinoma cells. For this study, cell viability and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, DAPI (4,6-diamidino-2-phenylindole) staining, agarose gel electrophoresis, and flow cytometry. Measurements of the mitochondrial membrane potential (MMP), caspase activity assays and western blots were conducted to determine whether HepG2 cell death occurred by apoptosis. Treatment of HepG2 cells with EEKS concentration-dependently reduced cell survival while significantly increasing the ratio of apoptotic cells. EEKS treatment increased the levels of the death receptors (DRs), DR4 and DR5, and activated caspases, as well as promoting proteolytic degradation of poly(ADP-ribose)-polymerase associated with the downregulation of protein expression of members of the inhibitor of apoptosis protein family. Treatment with EEKS also caused truncation of Bid, translocation of pro-apoptotic Bax to the mitochondria, and loss of mitochondrial membrane permeabilization, thereby inducing the release of cytochrome c into the cytosol. However, treatment of HepG2 cells with a pan-caspase inhibitor reversed EEKS-induced apoptosis and growth suppression, indicating that EEKS appears to induce apoptosis though a caspase-dependent mechanism involving both intrinsic and extrinsic apoptotic pathways. In addition, the phosphorylation level of AMP-activated protein kinase (AMPK) was elevated when cells were exposed to EEKS. A specific inhibitor for AMPK attenuated the EEKS-induced activation of caspases, and consequently prevented the EEKS-induced apoptosis and reduction in cell viability. Overall, our findings suggest that EEKS inhibits the growth of HepG2 cells by inducing AMPK-mediated caspase-dependent apoptosis, suggesting the potential therapeutic application of EEKS in the treatment or prevention of cancers.

Zahoor A, Mansoor Q, Farooqi AA, et al.
Genetic variants in the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor (DR4) genes contribute to susceptibility to colorectal cancer in pakistani population.
Cell Mol Biol (Noisy-le-grand). 2015; 61(6):108-12 [PubMed] Related Publications
TRAIL mediated signaling in cancer cells has emerged as one amongst the most deeply studied molecular phenomenon. Data obtained through genetic studies has highlighted highly polymorphic nature of DR4 and in accordance with this concept, we aimed to investigate the association between Colorectal cancer and polymorphisms in TRAIL and DR4 gene. We selected 100 patients with colorectal cancer and 100 healthy, sex and age matched volunteers randomly. C626G and A1322G in DR4 gene were analyzed using Polymerase Change Reaction (PCR) - Restriction Fragment Length Polymorphism (RFLP) and Amplification Refractory Mutation System (ARMS) techniques. PCR-RFLP was used to study TRAIL 1595 C>T. TRAIL gene 1595 C>T genotypes percentage in colorectal cancer patients was statistically non-significant. CC was 43% in patients and 50% in controls. CT was 45% in patients and 43% in controls. TT was 12% in patients and 7% in controls. C allele was 0.655% in cancer patients and 0.715% in controls. T allele was 0.345% in patients and 0.285% in controls. DR4 gene 626 C>G genotypes percentage analysis indicated that CC was 28% in patients and 2% in controls. GC was 42% in patients and 40% in controls. GG was 30% in patients and 58% in controls. CC was statistically significant (p=0.00000207) in cancer patients. C allele was 0.49% in patients and 0.22% in controls. G allele was 0.51% in patients and 0.78% in controls. For DR4 A1322G, homozygous GG genotype was 36% in the patients and in controls. There was statistically insignificant difference (p> 0.05). The heterozygous GT genotype was 30% in patients and 29% in controls. This difference was statistically insignificant (p value > 0.05). Similarly, the homozygous genotype TT of the minor allele was (35%) in controls and patients (34 %). This difference was also statistically insignificant (p value > 0.05). C allele was 0.51% in patients and 0.5% in controls. T allele was 0.49% in patients and 0.495% in controls. Future studies must converge on a larger sample size, sporadic mutations of DR4 and TRAIL and expression profiling.

Fahrioğlu U, Dodurga Y, Elmas L, Seçme M
Ferulic acid decreases cell viability and colony formation while inhibiting migration of MIA PaCa-2 human pancreatic cancer cells in vitro.
Gene. 2016; 576(1 Pt 3):476-82 [PubMed] Related Publications
Novel and combinatorial treatment methods are becoming sought after entities in cancer treatment and these treatments are even more valuable for pancreatic cancer. The scientists are always on the lookout for new chemicals to help them in their fight against cancer. In this study, we examine the effects of ferulic acid (FA), a phenolic compound, on gene expression, viability, colony formation and migration/invasion in the cultured MIA PaCa-2 human pancreatic cancer cell. Cytotoxic effects of FA were determined by using trypan blue dye exclusion test and Cell TiterGlo (CTG) assay. IC50 dose in MIA PaCa-2 cells was detected as 500μM/ml at the 72nd hour. Expression profiles of certain cell cycle and apoptosis genes such as CCND1 (cyclin D1),CDK4, CDK6, RB, p21, p16, p53, caspase-3, caspase-9, caspase-8, caspase-10, Bcl-2, BCL-XL,BID, DR4,DR5,FADD,TRADD,PARP, APAF, Bax, Akt, PTEN, PUMA, NOXA, MMP2, MMP9, TIMP1 and TIMP2 were determined by real-time PCR. The effect of FA on cell viability was determined by CellTiter-Glo® Luminescent Cell Viability Assay. Additionally, effects of FA on colony formation and invasion were also investigated. It was observed that FA caused a significant decrease in the expression of CCND1, CDK 4/6, Bcl2 and caspase 8 and 10 in the MIA PaCa-2 cells while causing an increase in the expression of p53, Bax, PTEN caspase 3 and 9. FA was observed to decrease colony formation while inhibiting cell invasion and migration as observed by the BioCoat Matrigel Invasion Chamber guide and colony formation assays. In conclusion, FA is thought to behave as an anti-cancer agent by affecting cell cycle, apoptotic, invasion and colony formation behavior of MIA PaCa-2 cells. Therefore, FA is placed as a strong candidate for further studies aimed at finding a better, more effective treatment approach for pancreatic cancer.

Milutinovic S, Kashyap AK, Yanagi T, et al.
Dual Agonist Surrobody Simultaneously Activates Death Receptors DR4 and DR5 to Induce Cancer Cell Death.
Mol Cancer Ther. 2016; 15(1):114-24 [PubMed] Free Access to Full Article Related Publications
Death receptors of the TNF family are found on the surface of most cancer cells and their activation typically kills cancer cells through the stimulation of the extrinsic apoptotic pathway. The endogenous ligand for death receptors 4 and 5 (DR4 and DR5) is TNF-related apoptosis-inducing ligand, TRAIL (Apo2L). As most untransformed cells are not susceptible to TRAIL-induced apoptosis, death receptor activators have emerged as promising cancer therapeutic agents. One strategy to stimulate death receptors in cancer patients is to use soluble human recombinant TRAIL protein, but this agent has limitations of a short half-life and decoy receptor sequestration. Another strategy that attempted to evade decoy receptor sequestration and to provide improved pharmacokinetic properties was to generate DR4 or DR5 agonist antibodies. The resulting monoclonal agonist antibodies overcame the limitations of short half-life and avoided decoy receptor sequestration, but are limited by activating only one of the two death receptors. Here, we describe a DR4 and DR5 dual agonist produced using Surrobody technology that activates both DR4 and DR5 to induce apoptotic death of cancer cells in vitro and in vivo and also avoids decoy receptor sequestration. This fully human anti-DR4/DR5 Surrobody displays superior potency to DR4- and DR5-specific antibodies, even when combined with TRAIL-sensitizing proapoptotic agents. Moreover, cancer cells were less likely to acquire resistance to Surrobody than either anti-DR4 or anti-DR5 monospecific antibodies. Taken together, Surrobody shows promising preclinical proapoptotic activity against cancer cells, meriting further exploration of its potential as a novel cancer therapeutic agent.

Sriraksa R, Limpaiboon T
TRAIL in Combination with Subtoxic 5-FU Effectively Inhibit Cell Proliferation and Induce Apoptosis in Cholangiocarcinoma Cells.
Asian Pac J Cancer Prev. 2015; 16(16):6991-6 [PubMed] Related Publications
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.

Qi S, Kou X, Lv J, et al.
Ampelopsin induces apoptosis in HepG2 human hepatoma cell line through extrinsic and intrinsic pathways: Involvement of P38 and ERK.
Environ Toxicol Pharmacol. 2015; 40(3):847-54 [PubMed] Related Publications
Our results showed that ampelopsin significantly inhibited cell viability of hepatoma HepG2 cells using MTT assay. We further investigated the mechanism of anticancer activity by ampelopsin, it showed that ampelopsin induced apoptosis of HepG2 cells using DAPI assay and flow cytometry, which was confirmed by activation of PARP. Next, activation of the caspase cascades were demonstrated, including caspase-8, -9 and -3. We also found that ampelopsin increased the levels of death receptor 4 (DR4), death receptor 5 (DR5) and decreased the expression of Bcl-2 protein, which led to an increase of the Bax/Bcl-2 ratio. Meanwhile, the release of cytochrome c from mitochondria was observed. Ampelopsin decreased the levels of iNOS and COX-2 but had no impact on the level of reactive oxygen species (ROS). In addition, ampelopsin activated ERK1/2 and P38, but little JNK1/2 activation was detected. Further investigation showed that suppression of P38 activation by SB203580 increased the cell viability and also prevented cleavage of caspase-3 and PARP, inhibition of ERK1/2 with U0126 had the opposite action. In conclusion, our results indicated that ampelopsin mainly elicited apoptosis through extrinsic and intrinsic pathway and that ERK1/2 and P38 had opponent effects on the apoptosis.

Cacan E, Greer SF, Garnett-Benson C
Radiation-induced modulation of immunogenic genes in tumor cells is regulated by both histone deacetylases and DNA methyltransferases.
Int J Oncol. 2015; 47(6):2264-75 [PubMed] Related Publications
Radiation treatment is a pivotal therapy for several cancer types, including colorectal cancer. It has been shown that sublethal doses of radiation modulate gene expression, making tumor cells more susceptible to T-cell-mediated immune attack. We have recently shown that low dose radiation enhances expression of multiple death receptors (Fas, DR4 and DR5) and co-stimulatory molecules (4-1BBL and OX-40L) in colorectal cancer (CRC) cells; however, it is unclear how ionizing radiation (IR) enhances expression of these molecules mechanistically. In the present study, we elucidate the molecular mechanisms by which radiation controls expression of these molecules in CRC. Here we report that, enhanced expression of these genes following radiation treatment of CRC cells is due, in part, to changes in DNA methylation and histone acetylation. We observed that radiation (5 Gy) significantly increased histone acetylation at the promoter regions of 4-1BBL, Fas and DR5 but not OX-40L. However, radiation did not induce changes in the global levels of acetylated histone H3 suggesting specificity of IR-induced changes. Furthermore, evaluation of epigenetic controlling enzymes revealed that IR did not alter overall cellular levels of HDACs (HDAC1, HDAC2 or HDAC3) or DNMTs (DNMT1, DNMT3a, or DNMT3b). Instead, radiation decreased binding of HDAC2 and HDAC3 at the promoter regions of Fas and 4-1BBL, respectively. Radiation also resulted in reduced DNMT1 at both the Fas and 4-1BBL promoter regions but not a control gene. We conclude that single dose radiation can influence the expression of immune response relevant genes in colorectal tumor cells by altering the binding of epigenetic enzymes, and modulating histone acetylation, at specific gene promoters.

Yao W, Yue P, Khuri FR, Sun SY
The BET bromodomain inhibitor, JQ1, facilitates c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 and c-Myc inhibition.
Oncotarget. 2015; 6(33):34669-79 [PubMed] Free Access to Full Article Related Publications
Inhibition of BET bromodomains (BRDs) has emerged as a promising cancer therapeutic strategy. Accordingly, inhibitors of BRDs such as JQ1 have been actively developed and some have reached clinical testing. However, the mechanisms by which this group of inhibitors exerts their anticancer activity, including induction of apoptosis, have not been fully elucidated. This report reveals a previously uncovered activity of JQ1 in inducing c-FLIP degradation and enhancing TRAIL-induced apoptosis. JQ1 potently decreased c-FLIP (both long and short forms) levels in multiple cancer cell lines without apparently increasing the expression of DR5 and DR4. Consequently, JQ1, when combined with TRAIL, synergistically induced apoptosis; this enhanced apoptosis-inducing activity could be abolished by enforced expression of ectopic FLIPL or FLIPS. Hence it appears that JQ1 decreases c-FLIP levels, resulting in enhancement of TRAIL-induced apoptosis. Inhibition of proteasome with MG132 prevented JQ1-induced c-FLIP reduction. Moreover, JQ1 decreased c-FLIP stability. Therefore, JQ1 apparently decreases c-FLIP levels through facilitating its proteasomal degradation. Genetic inhibition of either BRD4 or c-Myc by knocking down their expression failed to mimic JQ1 in decreasing c-FLIP and enhancing TRAIL-induced apoptosis, suggesting that JQ1 induces c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 or c-Myc inhibition. In summary, our findings in this study highlights a novel biological function of JQ1 in modulating apoptosis and warrant further study of the potential treatment of cancer with the JQ1 and TRAIL combination.

Fidan-Yaylalı G, Dodurga Y, Seçme M, Elmas L
Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells.
Tumour Biol. 2016; 37(2):2647-53 [PubMed] Related Publications
Exendin-4 is a GLP-1 analog used for the treatment of type 2 diabetes mellitus in its synthetic form. As women with diabetes have higher breast cancer incidence and mortality, we examined the effect of the incretin drug exendin-4 on breast cancer cells. The aim of the study is to investigate anticancer mechanism of exendin-4 in MCF-7 breast cancer cells. Cytotoxic effects of exendin-4 were determined by XTT assay. IC50 dose in MCF-7 cells were detected as 5 μM at 48th hour. Gene messenger RNA (mRNA) expressions were evaluated by real-time PCR. According to results, caspase-9, Akt, and MMP2 expression was reduced in dose group cells, compared with the control group cells. p53, caspase-3, caspase-8, caspase-10, BID, DR4, DR5, FADD, TRADD, PARP, PTEN, PUMA, NOXA, APAF, TIMP1, and TIMP2 expression was increased in dose group cells, compared with the control group cells. Effects of exendin-4 on cell invasion, colony formation, and cell migration were detected by Matrigel chamber, colony formation assay, and wound-healing assay, respectively. To conclude, it is thought that exendin-4 demonstrates anticarcinogenesis activity by effecting apoptosis, invasion, migration, and colony formation in MCF-7 cells. Exendin-4 may be a therapeutic agent for treatment of breast cancer as single or in combination with other agents. More detailed researches are required to define the pathways of GLP-1 effect on breast cancer cells because of the molecular biology of breast cancer that involves a complex network of interconnected signaling pathways that have role in cell growth, survival, and cell invasion.

Arafat W, Zhou T, Naoum GE, Buchsbaum DJ
Targeted radiotherapy potentiates the cytotoxicity of a novel anti-human DR5 monoclonal antibody and the adenovirus encoding soluble TRAIL in prostate cancer.
J Egypt Natl Canc Inst. 2015; 27(4):205-15 [PubMed] Related Publications
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces a death signal following binding to death receptors (DR4, DR5). We have developed a novel anti-human DR-5 monoclonal antibody (TRA-8) and adenoviral encoding TRAIL (Ad/TRAIL). Herein, we are testing the combined effect of radiotherapy and TRA-8 or Ad TRAIL in prostate cancer cells. Human prostate cancer cell lines LnCap, PC-3 and DU145 were used in this study. Cells were treated either with TRA-8 alone or Ad/TRAIL, radiation alone, or a combination of each at different doses and intervals. Cell survival using the MTS assay and colony forming assay were used to determine radiosensitization. Immunohistochemistry was used to detect bax and bcl-2. Real-time PCR was performed on mRNA of treated prostate cancer cell lines. Finally, a murine model of subcutaneous prostate cancer was used to evaluate the in vivo effect. Cell survival assays detected by MTS assay showed that prostate cell lines treated with a combination of radiation and TRA-8 showed significantly lower survival than cells treated with either radiation or TRA-8 alone. Colony forming assay and cell proliferation assays showed increased killing after combination treatment with TRA-8 or Ad/TRAIL and radiation, than either single agent alone. Mechanistic studies showed that the killing effect was due to induction of apoptosis mostly by increased expression of bax in TRA-8 or Ad/TRAIL treated cells. Additionally, RT-PCR showed an increased copy number of bax in most cells treated with TRA-8 and radiation. It is concluded that radiation and TRA-8 or Ad/TRAIL produced a synergistic effect in refractory prostrate cancer.

Wen J, Song C, Liu J, et al.
Expression quantitative trait loci for TNFRSF10 influence both HBV infection and hepatocellular carcinoma development.
J Med Virol. 2016; 88(3):474-80 [PubMed] Related Publications
Tumor necrosis factor receptor superfamily member 10 (TNFRSF10) is a death domain-containing receptor for the apoptotic ligand TNFSF10, which involves multiple processes, including hepatocarcinogenesis and immune response against HBV infection. Several single nucleotide polymorphisms (SNPs) were identified as expression quantitative trait loci (eQTLs) for TNFRSF10. To assess the association of TNFRSF10 eQTL SNPs with the risk of hepatocellular carcinoma (HCC) and chronic HBV infection, we designed a case-control study that included 1,300 HBV-related HCC patients, 1,344 chronic HBV carriers, and 1,344 subjects with HBV natural clearance, and then genotyped two TNFRSF10 eQTL SNPs (rs79037040 and rs2055822). We found that rs79037040 GT/TT genotypes were associated with a decreased HCC risk (adjusted odds ratio [OR] = 0.83, 95% confidence intervals [CIs] = 0.71-0.97, P = 0.021) but an increased chronic HBV infection risk of borderline significance (adjusted OR = 1.14, 95%CIs = 0.98-1.33, P = 0.085). In contrast, the rs2055822 G allele was a risk factor for HCC (adjusted OR = 1.12, 95%CIs = 1.00-1.25, P = 0.041) but a protective factor for chronic HBV infection (adjusted OR = 0.89, 95%CIs = 0.80-0.99, P = 0.038). Furthermore, we observed a dose-dependent relationship between the number of alleles (rs79037040-T and rs2055822-A) and the risk of HCC and chronic HBV infection. In comparison with "0" alleles, having "1-4" alleles was significantly associated with decreased HCC risk and increased HBV infection risk. These findings suggest that eQTL SNPs for TNFRSF10 may be susceptibility markers for HCC and chronic HBV infection.

Kang Z, Goldstein SD, Yu Y, et al.
Caspase-8 expression is predictive of tumour response to death receptor 5 agonist antibody in Ewing's sarcoma.
Br J Cancer. 2015; 113(6):894-901 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite good initial response to chemotherapy, 30% of Ewing's sarcoma (EWS) patients with localised tumours develop recurrent disease, associated with poor prognosis. The aim of this study was to address this challenge by conducting preclinical evaluation of a death receptor targeted agent in vitro and in vivo, and by identifying predictive biomarkers.
METHODS: Cell viability assays, drug dose responses, immunoblots, rescue with gene transfer, mice tumour models, and statistical comparisons of tumour growth and Kaplan-Meier survival curves.
RESULTS: This study shows that many EWS cell lines are selectively sensitive to a death receptor DR5 antibody and are more resistant to a DR4 antibody. Preclinical evaluation of these cell lines indicates their sensitivity to human DR5 agonist antibody conatumumab in vitro, which induces rapid activation of caspase-8 and apoptosis. We also found that sensitivity to conatumumab correlates with expression of caspase-8. Furthermore, the catalytic activity of caspase-8 is both necessary and sufficient to confer this sensitivity. In vivo, conatumumab is active against an EWS cell line and a patient-derived xenograft with higher caspase-8 expression, but is not effective against another with lower caspase-8 expression.
CONCLUSIONS: These studies suggest the potential of conatumumab as a therapeutic agent against EWS and caspase-8 as a predictive biomarker for sensitivity.

Sun J, Luo H, Nie W, et al.
Protective effect of RIP and c-FLIP in preventing liver cancer cell apoptosis induced by TRAIL.
Int J Clin Exp Pathol. 2015; 8(6):6519-25 [PubMed] Free Access to Full Article Related Publications
TRAIL (TNF-related apoptosis-inducing ligand) is a member of the tumor necrosis factor superfamily that can induce tumor selective death by up-regulating death receptor 4 (DR4) and DR5 expression. The study aimed to explore the role of RIP and c-FLIP genes in TRAIL induced liver cancer cell HepG2 and Hep3B apoptosis and related mechanism. RIP and c-FLIP silenced HepG2 and Hep3B cell model were established through siRNA. Western blot was applied to test c-FLIP, RIP, DR4, DR5, FADD, Caspase-3/8/9, ERK1/2, and DFF45 protein expression. Caspase-8 kit was used to detect Caspase-8 expression. Flow cytometry was performed to measure cell apoptosis rate. Acid phosphatase method was applied to determine cell cycle. TRAIL had no significant effect on Caspase-3/8/9, DR4, DR5, ERK1/2, and DFF45 protein expression, but up-regulated c-FLIP and RIP protein expression and reduced FADD expression level. After treated by the chemotherapy drug mitomycin and adriamycin, c-FLIP and RIP expression decreased significantly, while FADD increased. After knockout c-FLIP and RIP gene, HepG2 and Hep3B cell apoptosis rate induced by TRAIL increased obviously. Meanwhile, cell subG1 percentage increased markedly and exhibited G1 phase growth retardation. In addition, after two kinds of gene knockout, Caspase-8 was activated and produce Caspase-3 P20 and P24, leading DFF45 appeared DNA fragment P17 and P25. c-FLIP and RIP can inhibit Caspase-8 activation and prompting HepG2 and Hep3B resistant to cell apoptosis induced by TRAIL.

Wang W, Qi X, Wu M
Effect of DR4 promoter methylation on the TRAIL-induced apoptosis in lung squamous carcinoma cell.
Oncol Rep. 2015; 34(4):2115-25 [PubMed] Related Publications
The aim of the present study was to examine the relationship between DR4 methylation status and gene expression and to determine whether DR4 methylation status affects TRAIL-induced apoptosis in lung squamous carcinoma cells. MSP, RT-PCR and western blot analysis were applied to detect the methylation status and gene expression. An MTT assay was used to detect the cell proliferation inhibition rate and flow cytometry was utilized to detect the apoptotic rate. The results showed that there was no association of the apoptotic rate with the clinicopathological characteristics for 80.6% of 36 lung squamous carcinoma patients in the methylation status (P>0.05). In the lung squamous carcinoma patients, the probability of DR4 low expression was approximately 58.3%, which may be associated with DR4 promoter methylation. The results also showed that a low expression of DR4 was correlated with the prognosis of patients. The in vitro experiments suggested DR4 genes of H226 and SK-MES-1 cells were in the methylation status and their mRNA and proteins had a low expression. Following intervention with 5-Aza-CdR, the DR4 genes of H226 and SK-MES-1 cells were in the unmethylation status and their mRNA and protein expression was significantly upregulated compared with the pre-interference ones, with differences being statistically significant (P<0.05). In addition, following interference with 5-Aza-CdR, H226 and SK-MES-1 cells became significantly sensitive to TRAIL (P<0.05). The results revealed 5-Aza‑CdR was able to reverse DR4 methy-lation status to upregulate its expression, thereby increasing the TRAIL-induced apoptosis in lung squamous carcinoma cells. Therefore, combining 5-Aza-CdR and TRAIL is a new strategy for treating lung squamous carcinoma.

Karakas D, Cevatemre B, Aztopal N, et al.
Addition of niclosamide to palladium(II) saccharinate complex of terpyridine results in enhanced cytotoxic activity inducing apoptosis on cancer stem cells of breast cancer.
Bioorg Med Chem. 2015; 23(17):5580-6 [PubMed] Related Publications
Wnt signaling is one of the core signaling pathways of cancer stem cells (CSCs). It is re-activated in CSCs and plays essential role in the survival, self-renewal and proliferation of these cells. Therefore, we aimed to evaluate the cytotoxic effects of palladium(II) complex which is formulated as [PdCl(terpy)](sac)2H2O and its combination with niclosamide which is an inhibitor of Wnt signaling pathway associated with breast cancer stem cells. Characteristic cell surface markers (CD44(+)/CD24(-)) were determined by flow cytometry in CSCs. ATP viability assay was used to determine the cytotoxic activity. The mode of cell death was evaluated morphologically using fluorescence microscopy and biochemically using M30 ELISA assay as well as performing qPCR. Our study demonstrated that the combination of niclosamide (1.5 μM) and Pd(II) complex (12.5, 25 and 50 μM) at 48 h has enhanced cytotoxic activity resulted from the induction of apoptosis (indicated by the presence of pyknotic nuclei, increments in M30 and over expression of proapoptotic genes of TNFRSF10A and FAS). Importantly, the addition of niclosamide resulted in the suppression of autophagy (proved by the decrease in ATG5 gene levels) that might have contributed to the enhanced cytotoxicity. In conclusion, the application of this combination may be regarded as a novel and effective approach for the treatment of breast cancer due to its promising cytotoxic effect on cancer stem cells that cause recurrence of the disease.

Oral AY, Cevatemre B, Sarimahmut M, et al.
Anti-growth effect of a novel trans-dichloridobis[2-(2-hydroxyethyl)pyridine]platinum (II) complex via induction of apoptosis on breast cancer cell lines.
Bioorg Med Chem. 2015; 23(15):4303-10 [PubMed] Related Publications
Breast cancer still continues to be the leading cause of cancer-related mortality in women worldwide. Although advances have been made in the treatment of this disease during the past decade, new approaches and novel compounds are urgently needed. The aim of this study was to evaluate the cytotoxic activity of trans-[PtCl2(2-hepy)2] [2-hepy=2-(2-hydroxyethyl) pyridine] on breast cancer cell lines, MCF-7 and MDA-MB-231. The platinum (II) complex was synthesized and characterized by our laboratory working group. Anti-growth effect was assayed by the MTT and ATP viability assays and also monitored real-time using xCELLigence system. The mode of cell death was evaluated by using the fluorescence microscopy (Hoechst 33342+Calcein-AM+Propidium iodide staining), Western blotting (cleaved PARP and caspase 3, total caspase 8), flow cytometry (quantitative analysis of live, early/late apoptotic, dead cells and caspase 3/7 activity) and the RT-PCR (the genes analyzed were BCL-2L10, BIK, BAX, BCL-2, FASLG, HRK, TNFRSF10B, and TNFRSF10A). The platinum (II) complex had anti-growth effect in a dose dependent manner in vitro. Cells were killed by apoptosis as evidenced by the pyknotic nuclei, cleavage of poly-(ADP-ribose) polymerase (PARP) and induction of active caspase-3. These results suggest that the complex might represent a potentially active novel drug for the breast cancer treatment and warrants further studies due to its promising cytotoxic activity.

Yim NH, Jung YP, Kim A, et al.
Induction of apoptotic cell death by betulin in multidrug-resistant human renal carcinoma cells.
Oncol Rep. 2015; 34(2):1058-64 [PubMed] Related Publications
Betulin, a triterpene from the bark of various species of birch tree, has various biological effects, including antiviral, antifungal and anticancer activities. The aim of the present study was to elucidate the mechanisms underlying the apoptotic effect of betulin in RCC4 multidrug-resistant human renal carcinoma cells. To evaluate anticancer activity, we performed cell viability and caspase activity assays, a proteome profiler array and western blot analysis in RCC4 cells. Betulin significantly decreased RCC4 cell viability in a time- and concentration-dependent manner. Betulin activated caspase family proteins, including caspase-3, -7, -8 and -9, and increased the expression of apoptosis-related proteins, including PARP and Bcl-2 family members. In an apoptosis array, betulin activated the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors TRAIL R1/DR4 and R2/DR5, and tumour necrosis factor receptor 1 (TNFR1), suggesting that betulin treatment leads to induction of apoptosis through both intrinsic and extrinsic apoptosis pathways in RCC4 cells. Notably, betulin significantly enhanced cytotoxicity and PARP cleavage in etoposide-treated RCC4 cells, and downregulated the expression of multidrug resistance protein 1 (MDR1). Taken together, our findings suggest that the anticancer effects of betulin involve induction of apoptosis and sensitisation of RCC4 cells, providing potentially useful information applicable to the use of betulin in renal cancer treatment.

Yang J, Yang C, Zhang S, et al.
ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer.
Cancer Biol Ther. 2015; 16(8):1194-204 [PubMed] Free Access to Full Article Related Publications
Evidences suggest that tumor microenvironment may play an important role in cancer drug resistance. Sphingosine kinase 2 (SphK2) is proposed to be the key regulator of sphingolipid signaling. This study is aimed to investigate whether the combination of molecular targeting therapy using a specific inhibitor of SphK2 (ABC294640), with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can enhance the apoptosis of non-small cell lung cancer (NSCLC) cells. Our results revealed that NSCLC cells' sensitivity to TRAIL is correlated with the level of SphK2. Compared with TRAIL alone, the combination therapy enhanced the apoptosis induced by TRAIL, and knockdown of SphK2 by siRNA presented a similar effect. Combination therapy with ABC294640 increased the activity of caspase-3/8 and up-regulated the expression of death receptors (DR). Additional investigations revealed that translocation of DR4/5 to the cell membrane surface was promoted by adding ABC294640. However, expression of anti-apoptosis proteins such as Bcl(-)2 and IAPs was not significantly modified by this SphK2 inhibitor. Overall, this work demonstrates that SphK2 may contribute to the apoptosis resistance in NSCLC, thus indicating a new therapeutic target for resistant NSCLC cells.

Timirci-Kahraman O, Ozkan NE, Turan S, et al.
Genetic variants in the tumor necrosis factor-related apoptosis-inducing ligand and death receptor genes contribute to susceptibility to bladder cancer.
Genet Test Mol Biomarkers. 2015; 19(6):309-15 [PubMed] Related Publications
AIM: The aim of this study was to evaluate the role of polymorphisms of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and death receptor (DR4) genes in bladder cancer susceptibility in a Turkish population.
MATERIALS AND METHODS: The study group included 91 bladder cancer patients, while the control group comprised 139 individuals with no evidence of malignancy. Gene polymorphisms of TRAIL C1595T (rs1131580) and DR4 C626G (rs4871857) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
RESULTS: The frequency of the TRAIL 1595 TT genotype was significantly lower in patients with bladder cancer compared to controls (p<0.001; odds ratios [OR]=0.143; 95% confidence interval [CI]=0.045-0.454). A significantly increased risk for developing bladder cancer was found for the group bearing a C allele for TRAIL C1595T polymorphism (p<0.001; OR=1.256; 95% CI=1.138-1.386). The observed genotype and allele frequencies of DR4 626 C/G in all groups were in agreement with the Hardy-Weinberg equilibrium (p=0.540). However, the frequency of DR4 GG genotype was found to be 2.1-fold increased in the bladder cancer patients with high-grade tumor, when compared to those having low-grade tumor (p=0.036). Additionally, combined genotype analysis showed that the frequency of TRAILCT-DR4GG was significantly higher in patients with bladder cancer in comparison with those of controls (p=0.037; OR=2.240; 95% CI=1.138-1.386).
CONCLUSIONS: Our study provides new evidence that TRAIL 1595 C allele may be used as a low-penetrant risk factor for bladder cancer development in a Turkish population. Otherwise, gene-gene interaction analysis revealed that the DR4GG genotype may have a predominant effect on the increased risk of bladder cancer over the TRAIL CT genotype.

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