Gene Summary

Gene:TNFRSF10B; TNF receptor superfamily member 10b
Summary:The protein encoded by this gene is a member of the TNF-receptor superfamily, and contains an intracellular death domain. This receptor can be activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL/APO-2L), and transduces an apoptosis signal. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for this gene. [provided by RefSeq, Mar 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor receptor superfamily member 10B
Source:NCBIAccessed: 15 March, 2017


What does this gene/protein do?
Show (17)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

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

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

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

Specific Cancers (7)

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: TNFRSF10B (cancer-related)

Meng P, Dong QC, Tan GG, et al.
Anti-tumor effects of a recombinant anti-prostate specific membrane antigen immunotoxin against prostate cancer cells.
BMC Urol. 2017; 17(1):14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To evaluate anti-prostate cancer effects of a chimeric tumor-targeted killer protein.
METHODS: We established a novel fusion gene, immunocasp-3, composed of NH2-terminal leader sequence fused with an anti-prostate-specific membrane antigen (PSMA) antibody (J591), the furin cleavage sequences of diphtheria toxin (Fdt), and the reverse coding sequences of the large and small subunits of caspase-3 (revcaspase-3). The expressing level of the immunocasp-3 gene was evaluated by using the reverse transcription-PCR (RT-PCR) and western blot analysis. Cell viability assay and cytotoxicity assay were used to evaluate its anti-tumor effects in vitro. Apoptosis was confirmed by electron microscopy and Annexin V-FITC staining. The antitumor effects of immunocasp-3 were assessed in nude mice xenograft models containing PSMA-overexpressing LNCaP cells.
RESULTS: This study shows that the immunocasp-3 proteins selectively recognized and induced apoptotic death in PSMA-overexpressing LNCaP cells in vitro, where apoptotic cells were present in 15.3% of the cells transfected with the immunocasp-3 expression vector at 48 h after the transfection, in contrast to 5.5% in the control cells. Moreover, LNCaP cells were significantly killed under the condition of the co-culture of the immunocasp-3-secreting Jurkat cells and more than 50% of the LNCaP cells died when the two cell lines were co-cultured within 5 days. In addition, The expression of immunocasp-3 also significantly suppressed tumor growth and greatly prolonged the animal survival rate in vivo.
CONCLUSION: A novel fusion gene, immunocasp-3, may represent a viable approach to treating PSMA-positive prostate cancer.

Suzawa K, Shien K, Peng H, et al.
Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies.
Anticancer Res. 2017; 37(1):301-307 [PubMed] Related Publications
BACKGROUND: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress.
MATERIALS AND METHODS: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors.
RESULTS: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors.
CONCLUSION: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

Gan WY, Li HM, Zhang YG, et al.
Association between IL18-607C/A and -137G/C polymorphisms and susceptibility to non-small cell lung cancer in a Chinese population.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Lung cancer is one of the main causes of cancer-related mortality in males and females worldwide. A pleiotropic effect has been observed in the interleukin 18 gene (IL18); its effects include the activation of natural killer cell cytotoxicity and the promotion of the Th1 immune response through the alteration of the expression of interferon-γ and TNF-α in humans. IL18 is therefore involved in the elimination of tumor cells in the human body. We recruited 357 patients with non-small cell lung cancer (NSCLC) and 414 controls to evaluate the correlation between two genetic variations (IL18-607C/A and IL18-137G/C) and the pathogenesis of NSCLC. We used polymerase chain reaction-restriction fragment length polymorphism to genotype IL18-607C/A and IL18-137G/C. Statistical analysis revealed that individuals harboring the AA genotype of IL18-607C/A had an increased risk of NSCLC compared to those harboring the CC genotype (OR = 2.20, 95%CI = 1.30-3.74). Individuals expressing the A allele of IL18-607C/A had an elevated risk of developing NSCLC compared to those expressing the C allele (OR = 1.31, 95%CI = 1.06-1.62). In summary, our analysis shows that the IL18-607C/A genetic variation is related to the risk of NSCLC, whereas the IL18-137G/C variation is not. Therefore, the IL18-607C/A variation is related to the pathogenesis of NSCLC in the Chinese population studied.

Hagihara M, Iriyama N, Yoshida C, et al.
Association of pleural effusion with an early molecular response in patients with newly diagnosed chronic-phase chronic myeloid leukemia receiving dasatinib: Results of a D-First study.
Oncol Rep. 2016; 36(5):2976-2982 [PubMed] Related Publications
Despite the efficacy and safety of dasatinib treatment for chronic-phase chronic myeloid leukemia (CML-CP), adverse effects such as pleural effusion (PE) are still a serious concern. We determined the clinical significance of PE incidence using patient data derived from the D-First clinical study. In the present study, chest radiography and quantification of specific lymphocyte subsets were performed routinely after initiation of dasatinib treatment. Among 52 patients with newly diagnosed CML-CP, 17 (33%) developed PE within 18 months after initial dasatinib administration, but all cases were moderate (Grade 1, 10 patients; Grade 2, 7 patients). CD56+ lymphocyte counts at 1 month correlated significantly with the incidence of PE, whereas lymphocytosis did not. The major molecular response (MMR) rate at 3 months (although not at later times) was significantly higher in PE-positive patients than PE-negative patients (59% versus 24%, respectively; P=0.013). Deep molecular response rates did not differ significantly between the PE groups at any time point during the observation period. Our results suggest that an immune-mediated mechanism involving natural killer cells underlies the development of PE in patients receiving dasatinib for 18 months. This mechanism likely promotes transient tumor regression in patients newly diagnosed with CML-CP.

Geng L, Li X, Zhou X, et al.
WP1066 exhibits antitumor efficacy in nasal‑type natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway.
Oncol Rep. 2016; 36(5):2868-2874 [PubMed] Related Publications
Nasal-type natural killer/T-cell lymphoma (nasal NKTCL) is an aggressive hematological neoplasm with poor prognosis, and its incidence is higher in Asia than in Western countries. Increasing evidence suggests that aberrant activation of signal transducers and activators of transcription 3 (STAT3) is related to numerous malignancies. However, the involvement of STAT3 in the pathogenesis of nasal NKTCL is poorly understood. In this study, immunohistochemistry (IHC) showed that 21/28 (75.0%) nasal NKTCL tissues harbored constitutively expression of phospho‑STAT3 (p‑STAT3) which was positively correlated with the Ki‑67 levels (P﹤0.05). Immunofluorescence (IF) also detected p‑STAT3 expression in SNK6 cells (NKTCL cell line). Furthermore, WP1066 (a novel selective STAT3 inhibitor) was able to inhibit proliferation and induce apoptosis of SNK6 cells. Moreover, western blot analysis and RT‑PCR demonstrated that WP1066 downregulated the protein and mRNA expressions of the pro‑survival molecules (including c‑Myc, cyclin D1, and Bcl‑2) in SNK6 cells. These results suggested that STAT3 activation represents a potential target in nasal NKTCL. WP1066 may be a promising agent in antitumor therapy against nasal NKTCL.

Jo JC, Kim M, Choi Y, et al.
Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type.
Ann Hematol. 2017; 96(1):25-31 [PubMed] Related Publications
Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are new therapeutic targets in cancer immunotherapy. The aim of this study was to investigate the clinicopathological characteristics of PD-1 and PD-L1 expression in extranodal natural killer/T‑cell lymphoma, nasal type (ENKTL). We performed PD-1 and PD-L1 immunostaining in 79 ENKTL biopsy samples and retrospectively analyzed medical records of all 79 patients from four tertiary referral hospitals. The expression of PD-1 and PD-L1 by tumor cells and/or infiltrating immune cells was evaluated. The expression rates of PD-L1 in tumor cells and infiltrating immune cells were 79.7 and 78.5 %, respectively, whereas PD-1 in tumor cells and infiltrating immune cells were 1.3 and 11.4 %. The PD-L1 positivity in tumor cells and infiltrating immune cells was significantly associated with low international prognostic index (IPI) (P = 0.044 and 0.037, respectively). Patients with normal range of serum lactate dehydrogenase demonstrated a significantly higher PD-L1 positivity in tumor cells (P = 0.020). PD-L1-positive patients had a trend toward better overall survival compared with that in patients with PD-L1-negative in tumor cells and infiltrating immune cells (P = 0.498 and 0.435, respectively). The expression rate of PD-L1 was up to 79.7 % in ENKTL, while PD-1 expression rate was very low. This is the first report describing the clinicopathological features and survival outcome according to expression of PD-1 and PD-L1 in ENKTL.

Chantana C, Yenjai C, Reubroycharoen P, Waiwut P
Combination of Nimbolide and TNF-α-Increases Human Colon Adenocarcinoma Cell Death through JNK-mediated DR5 Up- regulation.
Asian Pac J Cancer Prev. 2016; 17(5):2637-41 [PubMed] Related Publications
Tumor necrosis factor (TNF-α), an inflammatory cytokine that plays an important role in the control of cell proliferation, differentiation, and apoptosis, has previously been used in anti-cancer therapy. However, the therapeutic applications of TNF-α are largely limited due to its general toxicity and anti-apoptotic influence. To overcome this problem, the present study focused on the effect of active constituents isolated from a medicinal plant on TNF-α-induced apoptosis in human colon adenocarcinoma (HT-29) cells. Nimbolide from Azadirachta indica was evaluated for cytotoxicity by methyl tetrazolium 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay and phase contrast microscopy. Effects on apoptotic signaling proteins were investigated using Western blot analysis. Nimbolide showed cytotoxicity against HT-29 cells that was significantly different from the control group (<0.01), a concentration of 10 μM significantly inducing cell death (<0.01). In combination with TNF-α, nimbolide significantly enhanced-induced cell death. In apoptotic pathway, nimbolide activated c-Jun N-terminal kinase (JNK) phosphorylation, BH3 interacting-domain death agonist (Bid) and up-regulated the death receptor 5 (DR5) level. In the combination group, nimbolide markedly sensitized TNF-α-induced JNK, Bid, caspase-3 activation and the up-regulation of DR5. Our findings overall indicate that nimbolide may enhance TNF-α-mediated cellular proliferation inhibition through increasing cell apoptosis of HT-29 cells by up-reglation of DR5 expression via the JNK pathway.

Abdelrahman MM, Fawzy IO, Bassiouni AA, et al.
Enhancing NK cell cytotoxicity by miR-182 in hepatocellular carcinoma.
Hum Immunol. 2016; 77(8):667-73 [PubMed] Related Publications
BACKGROUND AND AIM: NK-cells are the principle defense line against different malignancies. Their activation status is determined by the balance between activating and inhibitory receptors such as NKG2D and NKG2A, respectively. MicroRNAs are crucial post-transcriptional regulators of gene expression, playing key roles in modulating NK-cell development and function. The aim of this study is to investigate the role of miRNAs in regulating the activation and cytotoxic function of NK-cells in HCC.
METHODS: In silico analysis was performed to predict a potential miRNA that might target NKG2D and NKG2A mRNAs. NK-cells were isolated from HCC patients and healthy controls, after which miRNA and mRNA were quantified. Manipulating miRNA expression was performed followed by investigating downstream targets and the cytotoxic activity of NK-cells against Huh-7 cell lines.
RESULTS: NK-cells of HCC patients showed miR-182 overexpression compared to controls. NKG2D and NKG2A were upregulated and downregulated, respectively, in HCC NK-cells. Upon forcing miR-182 expression in the HCC NK-cells, upregulation of both receptors was observed. Finally, miR-182 was reported to induce NK-cell cytotoxicity represented in Perforin-1 upregulation and increase in cytolytic killing of co-cultured Huh-7 cells.
CONCLUSION: Our findings suggest that miR-182 may augment NK-cell cytotoxicity against liver cancer via modulating NKG2D and NKG2A expressions.

Dilshara MG, Jayasooriya RG, Park SR, et al.
Caffeic acid phenethyl ester enhances TRAIL-mediated apoptosis via CHOP-induced death receptor 5 upregulation in hepatocarcinoma Hep3B cells.
Mol Cell Biochem. 2016; 418(1-2):13-20 [PubMed] Related Publications
Caffeic acid phenethyl ester (CAPE) exhibits various pharmaceutical properties, including anti-bacterial, anti-inflammatory, anti-viral, anti-cancer, and anti-oxidative activity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been a promising anti-cancer agent that preferentially induces cancer cell apoptosis with negligible cytotoxicity toward normal cells. Therefore, the present study investigated whether CAPE promotes TRAIL-mediated cytotoxicity in hepatocarcinoma Hep3B cells. The present study demonstrated that CAPE sensitized TRAIL-mediated cell death in Hep3B carcinoma cells. The percentages of the apoptotic cells and annexin-V(+) cells significantly increased in combined treatment with CAPE and TRAIL (CAPE/TRAIL). Treatment with pancaspase inhibitor, z-VAD-fmk, attenuated CAPE/TRAIL-induced apoptosis, suggesting that the combined treatment triggers caspase-dependent apoptosis. Additionally, we found that CAPE stimulated the expression of death receptor 5 (DR5) and treatment with DR5/Fc chimera protein significantly blocked CAPE/TRAIL-induced apoptosis, which indicates that CAPE/TRAIL stimulated apoptosis through the binding of TRAIL to DR5. Moreover, expression of transcription factor C/EBP homologous protein (CHOP) markedly increased in response to CAPE and transient knockdown of CHOP abolished CAPE/TRAIL-mediated apoptosis. These results suggest that CHOP is a key regulator in CAPE/TRAIL-mediated apoptosis. Taken together, the present study found that CAPE significantly enhanced TRAIL-mediated apoptosis in Hep3B carcinoma cells and suggested that CAPE has promising potential in chemoprevention of hepatocellular carcinomas.

Zhao HB, Zhang XF, Shi F, et al.
Comparison of the expression of human equilibrative nucleotide transporter 1 (hENT1) and ribonucleotide reductase subunit M1 (RRM1) genes in seven non-Hodgkin lymphoma cell lines.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
We investigated the variability in the expression of human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase subunit M1 (RRM1) in non-Hodgkin lymphoma cell lines. hENT1 and RRM1 mRNA expression levels in natural killer (NK) cells and seven non-Hodgkin lymphoma cell lines (YTS, SNK-6, Jeko-1, ly-1, Raji, Karpas, and Jurket) were studied using reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) and the results were compared using the Student t-test. mRNA expression of hENT1 was detectable in YTS, SNK-6, Jeko-1, ly-1, Raji, Karpas, Jurket, and NK cells, which revealed variability in gene expression. There were significant differences in the mRNA expression values of hENT1 (P = 0.021) and RRM1 (P = 0.002) compared to those in NK cells. mRNA expression of both hENT1 and RRM1 was closely associated with non-Hodgkin lymphoma cell proliferation. Differential expression analysis of hENT1 and RRM1 in non-Hodgkin lymphoma cell lines may provide novel drug leads for precision medicine.

Li1 XH, Yang CZ, Wang J
Network spatio-temporal analysis predicts disease stage-related genes and pathways in renal cell carcinoma.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
The purpose of this study was to screen the key genes and pathways of renal cell carcinoma (RCC) and lay the foundation for its diagnosis and therapy. Microarray data of normal subjects and RCC patients at different stages of disease were used to screen differentially expressed genes (DEGs). Based on the DEGs in the four disease stages, four co-expression networks were constructed using the Empirical Bayes method and hub genes were obtained by centrality analysis. The enriched pathways of the DEGs and the mutual hub genes in the cluster of each disease stage were investigated. The mutual hub genes of the four disease stages in RCC tissue were validated using reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis. A total of 432 DEGs were screened, including 233 upregulated and 199 downregulated genes, by statistical analysis. Centrality analysis of co-expression networks in different disease stages suggested that PLXDC1, IKZF1, RUNX2, and RNF125 were mutual hub genes. Pathway analysis showed that the DEGs were significantly enriched in seven terms. The hub modules in stage I disease were significantly enriched in the complement coagulation cascade pathway and the hub modules of the other three disease stages were enriched in natural killer cell-mediated cytotoxicity. The expression levels of PLXDC1, IKZF1, RUNX2, and RNF125 were significantly different between normal subjects and RCC patients by RT-PCR and western blot. Our study revealed four hub genes (PLXDC1, IKZF1, RUNX2, and RNF125) and two biological pathways that might be underlying biomarkers involved in RCC.

El-Shemi AG, Ashshi AM, Na Y, et al.
Combined therapy with oncolytic adenoviruses encoding TRAIL and IL-12 genes markedly suppressed human hepatocellular carcinoma both in vitro and in an orthotopic transplanted mouse model.
J Exp Clin Cancer Res. 2016; 35:74 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gene-based virotherapy mediated by oncolytic viruses is currently experiencing a renaissance in cancer therapy. However, relatively little attention has been given to the potentiality of dual gene virotherapy strategy as a novel therapeutic approach to mediate triplex anticancer combination effects, particularly if the two suitable genes are well chosen. Both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interleukin-12 (IL-12) have been emerged as promising pharmacological candidates in cancer therapy; however, the combined efficacy of TRAIL and IL-12 genes for treatment of human hepatocellular carcinoma (HCC) remains to be determined.
METHODS: Herein, we investigated the therapeutic efficacy of concurrent therapy with two armed oncolytic adenoviruses encoding human TRAIL gene (Ad-ΔB/TRAIL) and IL-12 gene (Ad-ΔB/IL-12), respectively, on preclinical models of human HCC, and also elucidated the possible underlying mechanisms. The effects of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy were assessed both in vitro on Hep3B and HuH7 human HCC cell lines and in vivo on HCC-orthotopic model established in the livers of athymic nude mice by intrahepatic implantation of human Hep3B cells.
RESULTS: Compared to therapy with non-armed control Ad-ΔB, combined therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 elicited profound anti-HCC killing effects on Hep3B and HuH7 cells and on the transplanted Hep3B-orthotopic model. Efficient viral replication and TRAIL and IL-12 expression were also confirmed in HCC cells and the harvested tumor tissues treated with this combination therapy. Mechanistically, co-therapy with Ad-ΔB/TRAIL+Ad-ΔB/IL-12 exhibited an enhanced effect on apoptosis promotion, activation of caspase-3 and-8, generation of anti-tumor immune response evidenced by upregulation of interferon gamma (IFN-γ) production and infiltration of natural killer-and antigen presenting cells, and remarkable repression of intratumor vascular endothelial growth factor (VEGF) and cluster of differentiation 31 (CD31) expression and tumor microvessel density.
CONCLUSIONS: Overall, our data showed a favorable therapeutic effect of Ad-ΔB/TRAIL+Ad-ΔB/IL-12 combination therapy against human HCC, and may therefore constitute a promising and effective therapeutic strategy for treating human HCC. However, further studies are warranted for its reliable clinical translation.

Tian W, Wang L, Yuan L, et al.
A prognostic risk model for patients with triple negative breast cancer based on stromal natural killer cells, tumor-associated macrophages and growth-arrest specific protein 6.
Cancer Sci. 2016; 107(7):882-9 [PubMed] Free Access to Full Article Related Publications
The aim of this study was to establish a prognostic risk model for patients with triple negative breast cancer (TNBC). A total of 278 specimens of human TNBC tissues were investigated by immunohistochemistry for growth-arrest specific protein 6 expression, infiltrations of stromal natural killer cells and tumor-associated macrophages. According to their prognostic risk scores based on the model, patients were divided into three groups (score 0, 1-2, 3). Correlations of prognostic risk scores, clinicopathologic features and overall survival (OS) were analyzed. To study the clinical value of this stratification model in early disease recurrence or metastasis, 177 patients were screened out for further analysis. Based on disease free survival (DFS), 90 patients fell within the DFS ≤3 years group and 87 patients within the DFS ≥5 years group. We analyzed the differences in prognostic risk scores between the two groups. The prognostic risk scores were negatively related to tumor size, lymph node metastasis and P53 status (P < 0.001 for all). Patients with low prognostic risk scores had longer OS (P = 0.001). Using multivariate analysis, it was determined that TNM stage (HR = 0.432, 95% confidence interval [CI] = 0.281-0.665, P = 0.003), FOXP3 positive lymphocytes (HR = 1.712, 95% CI = 1.085-2.702, P = 0.021) and prognostic risk scores (HR = 1.340, 95% CI = 1.192-1.644, P = 0.005) were independent prognostic factors for OS. Compared with the DFS ≥5 years group, the DFS ≤3 years group patients had significantly higher prognostic risk scores (P < 0.001). In conclusion, the prognostic risk score of the model was a significant indicator of prognosis for patients with TNBC.

Ma J, Zhao Z, Wu K, et al.
MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC.
Gene. 2016; 587(2):147-54 [PubMed] Related Publications
Cisplatin is one of the most effective chemotherapeutic agents for the treatment of lung cancer. However, the acquired resistance occurred in cancer cells limits the clinical application of cisplatin. MCL-1, which is an important member in the pro-survival Bcl-2 family, plays a critical role in multidrug resistance (MDR). The aim of the present study is to investigate the value of Pan-Bcl-2 inhibitor as sensitizer for the chemotherapy of cisplatin-resistant non-small cell lung cancer (NSCLC) cells. We found the obatoclax but not the ABT-737 significantly decreased the IC50 (half maximal inhibitory concentration) of cisplatin in cisplatin-resistant NSCLC cells. Furthermore, we demonstrated that the mechanism of obatoclax-promoted cell death induced by cisplatin was dependent on the inhibition of MCL-1, which couldn't be inhibited by ABT-737 but is the target of obatoclax. Moreover, inhibition of MCL-1 recovered the function of NOXA and BAK in cisplatin-resistant NSCLC cells, leading to the promotion of mitochondrial apoptosis induced by cisplatin. Interestingly, our date indicated the obatoclax also reversed the cross-resistance in cisplatin-resistant NSCLC cells. Therefore, we demonstrated that the targeted therapy with MCL-1 inhibitors, such as obatoclax, may represent a novel strategy for cancer therapy.

Selhub J, Rosenberg IH
Excessive folic acid intake and relation to adverse health outcome.
Biochimie. 2016; 126:71-8 [PubMed] Related Publications
The recent increase in the intake of folic acid by the general public through fortified foods and supplements, has raised safety concern based on early reports of adverse health outcome in elderly with low B12 status who took high doses of folic acid. These safety concerns are contrary to the 2015 WHO statement that "high folic acid intake has not reliably been shown to be associated with negative healeffects". In the folic acid post-fortification era, we have shown that in elderly participants in NHANES 1999-2002, high plasma folate level is associated with exacerbation of both clinical (anemia and cognitive impairment) and biochemical (high MMA and high Hcy plasma levels) signs of vitamin B12 deficiency. Adverse clinical outcomes in association with high folate intake were also seen among elderly with low plasma B12 levels from the Framingham Original Cohort and in a study from Australia which combined three elderly cohorts. Relation between high folate and adverse biochemical outcomes were also seen in the Sacramento Area Latino Study on Aging (High Hcy, high MMA and lower TC2) and at an outpatient clinic at Yale University where high folate is associated with higher MMA in the elderly but not in the young. Potential detrimental effects of high folic acid intake may not be limited to the elderly nor to those with B12 deficiency. A study from India linked maternal high RBC folate to increased insulin resistance in offspring. Our study suggested that excessive folic acid intake is associated with lower natural killer cells activity in elderly women. In a recent study we found that the risk for unilateral retinoblastoma in offspring is 4 fold higher in women that are homozygotes for the 19 bp deletion in the DHFR gene and took folic acid supplement during pregnancy. In the elderly this polymorphism is associated with lower memory and executive scores, both being significantly worse in those with high plasma folate. These and other data strongly imply that excessive intake of folic acid is not always safe in certain populations of different age and ethnical/genetic background.

Gallegos CE, Michelin S, Dubner D, Carosella ED
Immunomodulation of classical and non-classical HLA molecules by ionizing radiation.
Cell Immunol. 2016; 303:16-23 [PubMed] Related Publications
Radiotherapy has been employed for the treatment of oncological patients for nearly a century, and together with surgery and chemotherapy, radiation oncology constitutes one of the three pillars of cancer therapy. Ionizing radiation has complex effects on neoplastic cells and on tumor microenvironment: beyond its action as a direct cytotoxic agent, tumor irradiation triggers a series of alterations in tumoral cells, which includes the de novo synthesis of particular proteins and the up/down-regulation of cell surface molecules. Additionally, ionizing radiation may induce the release of "danger signals" which may, in turn lead to cellular and molecular responses by the immune system. This immunomodulatory action of ionizing radiation highlights the importance of the combined use (radiotherapy plus immunotherapy) for cancer healing. Major histocompatibility complex antigens (also called Human Leukocyte Antigens, HLA in humans) are one of those molecules whose expression is modulated after irradiation. This review summarizes the modulatory properties of ionizing radiation on the expression of HLA class I (classical and non-classical) and class II molecules, with special emphasis in non-classical HLA-I molecules.

Lim SL, Mustapha NM, Goh YM, et al.
Metastasized lung cancer suppression by Morinda citrifolia (Noni) leaf compared to Erlotinib via anti-inflammatory, endogenous antioxidant responses and apoptotic gene activation.
Mol Cell Biochem. 2016; 416(1-2):85-97 [PubMed] Related Publications
Metastasized lung and liver cancers cause over 2 million deaths annually, and are amongst the top killer cancers worldwide. Morinda citrifolia (Noni) leaves are traditionally consumed as vegetables in the tropics. The macro and micro effects of M. citrifolia (Noni) leaves on metastasized lung cancer development in vitro and in vivo were compared with the FDA-approved anti-cancer drug Erlotinib. The extract inhibited the proliferation and induced apoptosis in A549 cells (IC50 = 23.47 μg/mL) and mouse Lewis (LL2) lung carcinoma cells (IC50 = 5.50 μg/mL) in vitro, arrested cancer cell cycle at G0/G1 phases and significantly increased caspase-3/-8 without changing caspase-9 levels. The extract showed no toxicity on normal MRC5 lung cells. Non-small-cell lung cancer (NSCLC) A549-induced BALB/c mice were fed with 150 and 300 mg/kg M. citrifolia leaf extract and compared with Erlotinib (50 mg/kg body weight) for 21 days. It significantly increased the pro-apoptotic TRP53 genes, downregulated the pro-tumourigenesis genes (BIRC5, JAK2/STAT3/STAT5A) in the mice tumours, significantly increased the anti-inflammatory IL4, IL10 and NR3C1 expression in the metastasized lung and hepatic cancer tissues and enhanced the NFE2L2-dependent antioxidant responses against oxidative injuries. The extract elevated serum neutrophils and reduced the red blood cells, haemoglobin, corpuscular volume and cell haemoglobin concentration in the lung cancer-induced mammal. It suppressed inflammation and oedema, and upregulated the endogenous antioxidant responses and apoptotic genes to suppress the cancer. The 300 mg/kg extract was more effective than the 50 mg/kg Erlotinib for most of the parameters measured.

Li XY, Wu L, Li SW, et al.
Effect of CD16a, the surface receptor of Kupffer cells, on the growth of hepatocellular carcinoma cells.
Int J Mol Med. 2016; 37(6):1465-74 [PubMed] Free Access to Full Article Related Publications
FcγRIIIa (CD16) is a low-affinity Fc receptor of IgG. As the idio-binding receptor of IgG Fc, it plays an important role in the antibody-dependent cellular cytotoxicity of natural killer cells. The aim of the present study was to investigate the distribution of Kupffer cells (KCs) and the expression of their surface receptor FcγRIIIa in hepatocellular carcinoma. Furthermore, we also aimed to observe the functional mechanism of FcγRIIIa. Immunohistochemical analysis was employed to study KCs and FcγRIIIa. In order to explore the role of FcγRIIIa in the growth of cancer cells, KCs and H22 tumor cells were co-cultured in different serum. The mRNA expression levels of tumor necrosis factor (TNF)-α and FcγRIIIa were analyzed by RT-qPCR; the TNF-α and FcγRIIIa protein expression levels were examined by enzyme‑linked immunosorbent assay and western blot analysis, respectively. Our results showed that the number of Kuppfer cells in cancerous tissues (21.6±7.8) was lower than those in para-cancerous (68.8±9.1) tissues and adjacent normal hepatic tissues (62.0±1.9) (P<0.01); this decreased with the reduction in the differentiation degree of cancer (P<0.05). FcγRIIIa-positive cells were similar in morphology to KCs, and their distributive tendency was coincident (P<0.05). The increase in CD16a mRNA levels in the group treated with immune serum was 3.9-, 4.9- and 3.9-fold greater than that in the ordinary serum group at different time points, and CD16a protein expression also markedly increased (P<0.05). However, these effects were inhibited by the addition of anti-IgG Fc serum (P<0.05). The results of the present study suggested that FcγRIIIa resided in KCs, and it contributed to the inhibition of the growth of liver tumor cells.

Yang X, Tietje AH, Yu X, Wei Y
Mouse interleukin-12/FasTI: A novel bi-functional fusion protein for cancer immuno/gene therapy.
Int J Oncol. 2016; 48(6):2381-6 [PubMed] Related Publications
Whereas cancer immunotherapy with cytokines in recent research was demonstrated effective in activating immune response against tumor cells, one major obstacle with the use of these cytokines is their severe side effects when delivered systemically at high doses. Another challenge is that advanced tumor cells often evade immunosurveillance of the immune system as well as of the Fas-mediated apoptosis by various mechanisms. We report the design and preliminary evaluation of the antitumor activity of a novel fusion protein-mIL-12/FasTI, consisting of mouse interleukin-12 and the transmembrane and intracellular domains of mouse Fas. The fusion construct (pmIL-12/FasTI) was transfected into mouse lung carcinoma cell line TC-1. Stable cell clones expressing the fusion protein were established as assayed by RT-PCR and immunohistochemistry. ELISA and cell proliferation analyses demonstrated that NK cells were effectively activated by the fusion protein with increased IFN-γ production and cytotoxicity. Enhanced caspase-3 activity of the clones when co-cultured with NK cells indicated that apoptosis was induced through Fas/FasL signaling pathway. The preliminary results suggest a synergized anticancer activity of the fusion protein. It may represent a promising therapeutic agent for cancer treatment.

Qian L, Wang N, Tian H, et al.
Dual Effects of Cellular Immunotherapy in Inhibition of Virus Replication and Prolongation of Survival in HCV-Positive Hepatocellular Carcinoma Patients.
J Immunol Res. 2016; 2016:6837241 [PubMed] Free Access to Full Article Related Publications
Immune cells play an important role in the development and progression of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). We conducted a retrospective study to evaluate the influence of adoptive cellular immunotherapy (CIT) on viral load and progression-free survival (PFS) for HCC patients infected with HCV. Patients (n = 104) were divided into a control group (conventional therapy, n = 73) and study group (combination of CIT and conventional therapy, n = 31). Autologous mononuclear cells were induced into natural killer, γδT, and cytokine-induced killer cells and infused intravenously to study group patients. More patients had shown viral load decrease or were stable in study group (100% versus 75%) (p = 0.014). The median PFS of the study group and control group was 16 and 10 months, respectively (p = 0.0041), and only CIT was an independent prognostic factor for PFS (hazard ratio, 0.422; p = 0.005). Three patients developed transient moderate fever after infusion, and there were no significant differences in alanine aminotransferase and aspartate aminotransferase levels before and after treatment in both groups. Our results show that CIT contributes to improvement of prognosis and inhibition of viral replication in HCV-related HCC patients, without impairment of liver function.

Borghi A, D'Accolti M, Rizzo R, et al.
High prevalence of specific KIR types in patients with HHV-8 positive cutaneous vascular lesions: a possible predisposing factor?
Arch Dermatol Res. 2016; 308(5):373-7 [PubMed] Related Publications
Human herpesvirus 8 (HHV8) has been hypothesized to be a potential cofactor for the development of diverse cutaneous vascular proliferative lesions, including eruptive cherry angiomas. Recent reports evidenced the influence of killer cell immunoglobulin-like receptor (KIR) gene diversity in defining the susceptibility to symptomatic herpesvirus infections. In this study, skin samples from vascular lesions and healthy controls were characterized simultaneously for the presence of HHV8 and for the KIR genotype, focusing upon the presence of the KIR2DL2/DS2 and KIR2DL3 genes, which have been associated to herpesvirus susceptibility. The results showed that about 64 % of the vascular lesions resulted positive for the presence of HHV8, whereas no control healthy skin samples harbored HHV8 DNA. HHV8-positive patients had a significantly increased frequency of KIR2DL2/DS2 homozigosity and a concomitant decrease of the homozygous KIR2DL3 genotype, compared to healthy controls or HHV8-negative patients. Notably, the simultaneous presence of KIR2DL2/DS2 homozygosity and HHV8 infection resulted in a significantly increased risk to develop cutaneous lesions (OR 5.7) compared to the individual factors alone, suggesting that specific KIR genotypes might predispose to HHV8 symptomatic infection, allowing the virus to exert its angioproliferative activity at skin level.

Huang K, Zhang J, O'Neill KL, et al.
Cleavage by Caspase 8 and Mitochondrial Membrane Association Activate the BH3-only Protein Bid during TRAIL-induced Apoptosis.
J Biol Chem. 2016; 291(22):11843-51 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
The BH3-only protein Bid is known as a critical mediator of the mitochondrial pathway of apoptosis following death receptor activation. However, since full-length Bid possesses potent apoptotic activity, the role of a caspase-mediated Bid cleavage is not established in vivo In addition, due to the fact that multiple caspases cleave Bid at the same site in vitro, the identity of the Bid-cleaving caspase during death receptor signaling remains uncertain. Moreover, as Bid maintains its overall structure following its cleavage by caspase 8, it remains unclear how Bid is activated upon cleavage. Here, Bid-deficient (Bid KO) colon cancer cells were generated by gene editing, and were reconstituted with wild-type or mutants of Bid. While the loss of Bid blocked apoptosis following treatment by TNF-related apoptosis inducing ligand (TRAIL), this blockade was relieved by re-introduction of the wild-type Bid. In contrast, the caspase-resistant mutant Bid(D60E) and a BH3 defective mutant Bid(G94E) failed to restore TRAIL-induced apoptosis. By generating Bid/Bax/Bak-deficient (TKO) cells, we demonstrated that Bid is primarily cleaved by caspase 8, not by effector caspases, to give rise to truncated Bid (tBid) upon TRAIL treatment. Importantly, despite the presence of an intact BH3 domain, a tBid mutant lacking the mitochondrial targeting helices (α6 and α7) showed diminished apoptotic activity. Together, these results for the first time establish that cleavage by caspase 8 and the subsequent association with the outer mitochondrial membrane are two critical events that activate Bid during death receptor-mediated apoptosis.

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] Article available free on PMC after 27/05/2017 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.

Wang Y, Sun J, Ma C, et al.
Reduced Expression of Galectin-9 Contributes to a Poor Outcome in Colon Cancer by Inhibiting NK Cell Chemotaxis Partially through the Rho/ROCK1 Signaling Pathway.
PLoS One. 2016; 11(3):e0152599 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Galectin-9 is a widely expressed protein that is involved in immune regulation and tumorpathogenesis and serves as a marker of a poor prognosis in various types of cancers. However, the clinical impact and the precise mechanism by which this protein contributes to colon tumor progression are unclear. In the present study, we detected the expression of galectin-9 and CD56 cells using immunohistochemistry. Spearman's rank correlation was used to clarify the association between galectin-9 expression and natural killer (NK) cell infiltration. The influence of galectin-9 on NK-92 cell migration was evaluated in vitro using transwell chemotaxis assays. The role of rh-galectin-9 in F-actin polarization in NK-92 cells was investigated using laser scanning confocal microscopy. We showed that galectin-9 was expressed in 101 (78.91%) colon tumor tissues and that was expressed at lower levels in these tissues than in para-tumor tissues. Low levels of galectin-9 expression were positively correlated with a poor histological grade and lymph node metastasis (P<0.05). A Kaplan-Meier method and Cox proportional hazards regression analysis showed that overall survival was longer in patients with high galectin-9 expression in an 8-year follow-up (P<0.05). Spearman's rank correlation indicated that there was a linear correlation between galectin-9 expression and CD56+ NK cell infiltration (R(2) = 0.658; P<0.0001). Galectin-9 stimulated migration in human NK-92 cells by affecting F-actin polarization through the Rho/ROCK1 signaling pathway. These results suggest that galectin-9 expression potentially represents a novel mechanism for tumors to escape immune surveillance in colon tumors.

Bargostavan MH, Eslami G, Esfandiari N, Shams Shahemabadi A
MMP9 Promoter Polymorphism (-1562 C/T) Does not Affect the Serum Levels of Soluble MICB and MICA in Breast Cancer.
Iran J Immunol. 2016; 13(1):45-53 [PubMed] Related Publications
BACKGROUND: The role of Matrix Metalloproteinase 9 (MMP9) in tumor invasion and progression is prominent. A single nucleotide polymorphism (SNP) in the promoter region of MMP9 (-1562 C/T) increases the transcription and expression of this gene. On the other hand, MHC class I chain-related protein A and B (MICA/B) in soluble forms may impair tumor immunogenicity by reducing Natural Killer Group 2D (NKG2D) densities on NK cells and MMP9 enzyme activity has a prominent role in shedding of MICA/B.
OBJECTIVES: To investigate the association between MMP9 (-1562 C/T) polymorphism and serum MICA/B level in breast cancer patients.
METHODS: In this case-control study, 105 patients with breast cancer and 100 healthy age-matched women were selected from Yazd hospitals, Iran. The polymorphism of MMP9 (-1562 C/T) was determined by PCR-RFLP. Concentration of MICB and MICA in the sera of breast cancer patients and healthy women were measured using ELISA method.
RESULTS: The frequency of CC, CT and TT genotypes and T allele of the MMP9 (-1562 C/T) did not show significant differences between breast cancer patients and healthy donors (p>0.05). On the other hand, the mean serum levels of MICB and MICA were significantly elevated in patients compared with healthy individuals (p<0.05). In patients with MMP9CC genotype, the mean serum MICB concentration was significantly higher than those patients with CT polymorphism (p<0.05). Although the mean of blood MICA concentration in patients with the CT genotype was higher than those patients with CC genotype, the difference was not statistically significant.
CONCLUSION: The T allele of the MMP9 (-1562 C/T) does not show a correlation with serum levels of MICA and MICB in breast cancer patients.

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

Yuan W, Zhang Z, Dai B, et al.
Whole-exome sequencing of duodenal adenocarcinoma identifies recurrent Wnt/β-catenin signaling pathway mutations.
Cancer. 2016; 122(11):1689-96 [PubMed] Related Publications
BACKGROUND: Genomic alterations of small bowel cancers remain poorly understood due to the rarity of these diseases. In the current study, the authors report the identification of somatic mutations from patients with duodenal adenocarcinoma by whole-exome sequencing.
METHODS: Whole-exome sequencing and follow-up analysis were conducted in 12 matched tumor-normal tissue duodenal adenocarcinoma tissue pairs to examine the genetic characteristics of this disease. Somatic mutations (single-nucleotide variants and short insertion/deletions) were obtained and filtered and then searched for recurrently mutated genes and pathways.
RESULTS: An excess of C-to-T transitions at the CpG dinucleotide was observed in the substitution of bases. The authors identified recurrent mutations in tumor protein p53 (TP53), KRAS, catenin (cadherin-associated protein) β-1 (CTNNB1), AT-rich interactive domain 2 (ARID2), adenomatous polyposis coli (APC), erb-b2 receptor tyrosine kinase 2 (ERBB2), ARID1A, cadherin-related family member 1 (CDHR1), NRAS, Bcl-2-related ovarian killer (BOK), radial spoke head 14 homolog (chlamydomonas) (RTDR1), cell division cycle 27 (CDC27), catalytic subunit of phosphoinositide-3-kinase (PIK3CA), and SMAD family member 4 (SMAD4). Pathway scan indicated that the Wnt signaling pathway, regulation of the actin cytoskeleton pathway, ErbB signaling pathway, and the pathway of focal adhesion were the most extensively affected pathways.
CONCLUSIONS: This genomic characterization of duodenal adenocarcinoma provides researchers with insight into its somatic landscape and highlights the vital role of the Wnt/β-catenin signaling pathway. The study data also indicate that duodenal adenocarcinomas have a genetic resemblance to gastric and colorectal cancers. These discoveries may benefit the future development of molecular diagnosis and personalized therapies. Cancer 2016;122:1689-96. © 2016 American Cancer Society.

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.

La Nasa G, Greco M, Littera R, et al.
The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR) A haplotype in patients with advanced-stage classic Hodgkin lymphoma.
J Hematol Oncol. 2016; 9:26 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
BACKGROUND: Interim positron emission tomography after 2 cycles of ABVD (iPET-2) is a good predictor of outcome in advanced-stage classic Hodgkin lymphoma. So far, there are no other prognostic biomarkers capable of identifying chemotherapy refractory patients with comparable accuracy. Despite the considerable amount of evidence suggesting that antitumor immune surveillance is downregulated in classic Hodgkin lymphoma (cHL), few data exist on the impairment of natural killer cell function and the role of their killer immunoglobulin-like receptors (KIRs).
METHODS: We investigated KIR gene frequencies, KIR haplotypes, and KIR-ligand combinations in a cohort of 135 patients with advanced-stage classic Hodgkin lymphoma and 221 healthy controls. We furthermore evaluated the correlation of KIR genes and KIR haplotypes with the achievement of negative iPET-2.
RESULTS: In the cohort of patients, the 5-year overall survival and progression-free survival were 93.6 and 79%, respectively. Homozygosity for KIR A haplotype and the HLA-C1 KIR ligand (KIR-AA/C1C1) was significantly higher in healthy controls (15.7 vs. 4.8%, p = 0.001). The KIR-AA genotype resulted to have a significant predictive power for achieving iPET-2 negativity (p = 0.039).
CONCLUSIONS: Homozygosity for KIR A haplotype offers protection against classic Hodgkin lymphoma. The association found for the KIR-AA genotype and achievement of negative iPET-2 suggests that KIR-AA could be used in clinical practice to enhance the chemosensitivity predictive power of iPET-2. Our results point to the possibility of adapting treatment strategies based on the combination of KIR biomarkers and PET scan.

Park EJ, Min KJ, Choi KS, et al.
Chloroquine enhances TRAIL-mediated apoptosis through up-regulation of DR5 by stabilization of mRNA and protein in cancer cells.
Sci Rep. 2016; 6:22921 [PubMed] Article available free on PMC after 27/05/2017 Related Publications
Chloroquine (CQ), an anti-malarial drug, has immune-modulating activity and lysosomotropic activity. In this study, we investigated CQ sensitizes TRAIL-mediated apoptosis in human renal cancer Caki cells. Combination of CQ and TRAIL significantly induces apoptosis in human renal cancer Caki cells and various human cancer cells, but not in normal mouse kidney cells (TMCK-1) and human mesangial cells (MC). CQ up-regulates DR5 mRNA and protein expression in a dose- and time- dependent manner. Interestingly, CQ regulates DR5 expression through the increased stability in the mRNA and protein of DR5, rather than through the increased transcriptional activity of DR5. Moreover, we found that CQ decreased the expression of Cbl, an E3 ligase of DR5, and knock-down of Cbl markedly enhanced DR5 up-regulation. Other lysosomal inhibitors, including monensin and nigericin, also up-regulated DR5 and sensitized TRAIL-mediated apoptosis. Therefore, this study demonstrates that lysosomal inhibition by CQ may sensitize TRAIL-mediated apoptosis in human renal cancer Caki cells via DR5 up-regulation.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. TNFRSF10B, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 15 March, 2017     Cancer Genetics Web, Established 1999