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Tumor Necrosis Factors

A family of proteins that were originally identified by their ability to cause NECROSIS of NEOPLASMS. Their necrotic effect on cells is mediated through TUMOR NECROSIS FACTOR RECEPTORS which induce APOPTOSIS. (Source: MeSH)

aka: TNF Receptor Ligands

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Latest Research Publications

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Makowska A, Franzen S, Braunschweig T, et al.
Interferon beta increases NK cell cytotoxicity against tumor cells in patients with nasopharyngeal carcinoma via tumor necrosis factor apoptosis-inducing ligand.
Cancer Immunol Immunother. 2019; 68(8):1317-1329 [PubMed] Related Publications
BACKGROUND: Nasopharyngeal carcinoma (NPC) is an EBV-associated neoplasm occurring endemically in Southeast Asia and sporadically all over the world. In children and adolescents, high cure rates have been obtained using chemotherapy, radiochemotherapy and maintenance therapy with interferon beta (IFNβ). The mechanism by which IFNβ contributes to a low systemic relapse rate has not yet been fully revealed.
PATIENTS AND METHODS: NK cells and serum samples from two patients with NPC were analyzed before and at different time points during IFNβ therapy, for assessment of TRAIL expression and NK cell cytotoxicity. Cytotoxicity was measured using the calcein release assay and the contribution of different death effector pathways was analyzed using specific inhibitors.
RESULTS: Treatment with IFNβ induced TRAIL expression on patients' NK cells and increased their cytotoxicity against NPC targets in vitro. NK cell-mediated cytotoxicity was predominately mediated via TRAIL. IFNβ also induced the production of soluble TRAIL (sTRAIL) by NK cells and its release upon contact with NPC cells. IFNβ treatment increased serum levels of sTRAIL in patients. Moreover, sTRAIL concentrated from patients' serum samples induced apoptosis ex vivo in NPC cells from a patient-derived xenograft.
CONCLUSION: Increased cytotoxicity of NK cells against NPC cells and increased serum levels of biologically active TRAIL in patients treated with IFNβ could be a means to eliminate micrometastatic disease and explain the low systemic relapse rate in this patient group.

Namgung Y, Kim SY, Kim I
Down-regulation of Survivin by BIX-01294 Pretreatment Overcomes Resistance of Hepatocellular Carcinoma Cells to TRAIL.
Anticancer Res. 2019; 39(7):3571-3578 [PubMed] Related Publications
BACKGROUND/AIM: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cancer-selective, cell-death-inducing agent with little toxicity to normal cells. However, various human cancers and cancer cell lines have been reported to be resistant to TRAIL. Molecular clarification of resistance mechanism is needed.
MATERIALS AND METHODS: Compound screening, proliferation assays, western blotting, and flow cytometry were used to examine the sensitizer activity of methyl transferase inhibitor BIX-01294 in combination with TRAIL, in hepatocellular carcinoma (HCC) cells. RNA sequencing analysis and single guide (sg)RNA-mediated gene deletion were used to investigate the role of survivin in sensitization.
RESULTS: In HCC cells, BIX-01294 enhanced TRAIL sensitivity by reducing survivin expression at the RNA level. Small interference RNA-mediated gene knockdown demonstrated the mechanism of sensitization to be via the reduction of survivin.
CONCLUSION: Euchromatin histone methyltransferase 2 (EHMT2) inhibition by BIX-01294 may be a potent anti-tumor therapeutic strategy for human HCC.

Chen S, Yang C, Sun C, et al.
miR-21-5p Suppressed the Sensitivity of Hepatocellular Carcinoma Cells to Cisplatin by Targeting FASLG.
DNA Cell Biol. 2019; 38(8):865-873 [PubMed] Related Publications
Accumulating evidence has suggested that microRNAs play important roles in the development of hepatocellular carcinoma (HCC) and are involved in drug resistance. miR-21-5p was overexpressed in a variety of cancers and promoted the tumorigenesis; however, the function of miR-21-5p in HCC still remains unknown. In this study, our results showed that miR-21-5p was highly expressed in HCC tissues and cell lines. Notably, the level of miR-21-5p was relatively higher in cisplatin (DDP)-resistant HCC patients. Overexpression of miR-21-5p attenuated the inhibitory effect of DDP on the proliferation and apoptosis of HCC cells. Mechanistically, the luciferase report assay-identified FAS ligand (FASLG) was a direct target of miR-21-5p. Overexpression of miR-21-5p decreased both the mRNA and protein levels of FASLG in HCC cells. FASLG was downregulated in HCC tissues and was significantly negatively correlated with the expression of miR-21-5p. Restoring the expression of FASLG upregulated the chemosensitivity of HCC cells expressing miR-21-5p. In conclusion, our results demonstrated that miR-21-5p targeted FASLG and suppressed the sensitivity of HCC cells to DDP treatment.

Martínez-Reza I, Díaz L, Barrera D, et al.
Calcitriol Inhibits the Proliferation of Triple-Negative Breast Cancer Cells through a Mechanism Involving the Proinflammatory Cytokines IL-1
J Immunol Res. 2019; 2019:6384278 [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1

van Dam PA, Verhoeven Y, Jacobs J, et al.
RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.

Shahwar D, Iqbal MJ, Nisa MU, et al.
Natural Product Mediated Regulation of Death Receptors and Intracellular Machinery: Fresh from the Pipeline about TRAIL-Mediated Signaling and Natural TRAIL Sensitizers.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Rapidly developing resistance against different therapeutics is a major stumbling block in the standardization of therapy. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated signaling has emerged as one of the most highly and extensively studied signal transduction cascade that induces apoptosis in cancer cells. Rapidly emerging cutting-edge research has helped us to develop a better understanding of the signaling machinery involved in inducing apoptotic cell death. However, excitingly, cancer cells develop resistance against TRAIL-induced apoptosis through different modes. Loss of cell surface expression of TRAIL receptors and imbalance of stoichiometric ratios of pro- and anti-apoptotic proteins play instrumental roles in rewiring the machinery of cancer cells to develop resistance against TRAIL-based therapeutics. Natural products have shown excellent potential to restore apoptosis in TRAIL-resistant cancer cell lines and in mice xenografted with TRAIL-resistant cancer cells. Significantly refined information has previously been added and continues to enrich the existing pool of knowledge related to the natural-product-mediated upregulation of death receptors, rebalancing of pro- and anti-apoptotic proteins in different cancers. In this mini review, we will set spotlight on the most recently published high-impact research related to underlying mechanisms of TRAIL resistance and how these deregulations can be targeted by natural products to restore TRAIL-mediated apoptosis in different cancers.

Hu L, Wang Y, Chen Z, et al.
Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway.
Oxid Med Cell Longev. 2019; 2019:9675450 [PubMed] Free Access to Full Article Related Publications
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFT

Møller T, James JP, Holmstrøm K, et al.
Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (

Nong J, Wang J, Gao X, et al.
Circulating CD137
Scand J Immunol. 2019; 89(6):e12765 [PubMed] Related Publications
CD137 is a promising target for immunostimulation strategies against cancer. Previous studies showed that CD137

Buhrmann C, Yazdi M, Popper B, et al.
Induction of the Epithelial-to-Mesenchymal Transition of Human Colorectal Cancer by Human TNF-β (Lymphotoxin) and its Reversal by Resveratrol.
Nutrients. 2019; 11(3) [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Tumor necrosis factor-beta (TNF-β), as an inflammatory mediator that has been shown to promote tumorigenesis, induces NF-κB. Natural multi-targeted agent resveratrol in turn shows anti-inflammatory and anti-cancer properties. Epithelial-to-mesenchymal transition (EMT) allows cancer cells to turn into a motile state with invasive capacities and is associated with metastasis and development of cancer stem cells (CSC). However, TNF-β-induced EMT and the anti-invasion mechanism of resveratrol on CRC are not yet completely understood.
METHODS: We investigated the underlying molecular mechanisms of resveratrol on TNF-β/TNF-βR-induced EMT and migration of CRC cells (HCT116, RKO, SW480) in monolayer or 3D alginate cultures.
RESULTS: TNF-β, similar to TNF-α, induced significant cell proliferation, morphological change, from an epithelial to a spindle-like mesenchymal shape with the formation of filopodia and lamellipodia associated with the expression of EMT parameters (elevated vimentin and slug, reduced E-cadherin), increased migration/invasion, and formation of CSC in all CRC cells. Interestingly, these effects were dramatically decreased in the presence of resveratrol or anti-TNF-βR with TNF-β co-treatment, inducing biochemical changes to the mesenchymal-epithelial transition (MET), with a planar cell surface and suppressed formation of CSC cells. This was associated with a significant increase in apoptosis. Furthermore, we found that resveratrol suppressed TNF-β-induced NF-κB and NF-κB-regulated gene biomarkers associated with growth, proliferation, and invasion. Finally, TNF-βR interacts directly with focal adhesion kinase (FAK) and NF-κB.
CONCLUSION: These results suggest that resveratrol down-regulates TNF-β/TNF-βR-induced EMT, at least in part via specific suppression of NF-κΒ and FAK in CRC cells.

Fouladseresht H, Ziaee SM, Erfani N, Doroudchi M
Serum Levels of APRIL Increase in Patients with Glioma, Meningioma and Schwannoma
Asian Pac J Cancer Prev. 2019; 20(3):751-756 [PubMed] Related Publications
Objective: Brain tumors are of high mortality and morbidity for which there is still no cure. The TNF family cytokine, A Proliferation Inducing Ligand (APRIL), is shown to help proliferation and development of tumor cells. We assessed serum levels of APRIL in patients with glioma, meningioma and schwannoma in comparison to healthy individuals. Methods: Peripheral blood samples of 68 patients with brain tumors, divided into three groups of gliomas (n=25), meningiomas (n=30) and schwannomas (n=13), as well as 45 healthy individuals were obtained. Serum samples were prepared and stored in -40°C until usage. Using a commercial ELISA method, APRIL concentration was measured in each serum sample. The obtained data were then analyzed using SPSS software. Results: APRIL serum levels were higher in all patients compared to the controls (P<0.001). Moreover, APRIL serum levels were higher in each of the tumor bearing groups (gliomas, meningiomas and schwannomas) in comparison to the controls (P<0.001, <0.001 and =0.001, respectively). Comparing APRIL between the patients groups showed no significant difference. Age and gender showed no significant correlation with serum APRIL levels, although the age of patients in glioma group was significantly lower than controls (P=0.017). The serum APRIL levels in gliomas with histological grade showed no difference, but in meningiomas, it was lower in tumors with higher grades (P= 0.011). Conclusion: Increased serum levels of APRIL in patients with meningioma and schwannoma as well as glioma may indicate a common role of this cytokine in brain tumors.

Onoe-Takahashi A, Suzuki-Karasaki M, Suzuki-Karasaki M, et al.
Autophagy inhibitors regulate TRAIL sensitivity in human malignant cells by targeting the mitochondrial network and calcium dynamics.
Int J Oncol. 2019; 54(5):1734-1746 [PubMed] Free Access to Full Article Related Publications
In a variety of cancer cell types, the pharmacological and genetic blockade of autophagy increases apoptosis induced by various anticancer drugs. These observations suggest that autophagy counteracts drug‑induced apoptosis. We previously reported that in human melanoma and osteosarcoma cells, autophagy inhibitors, such as 3‑methyladenine and chloroquine increased the sensitivity to apoptosis induced by tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL). In the present study, we report that different autophagy inhibitors regulate the mitochondrial network and calcium (Ca2+) dynamics in these cells. We found that compared to tumor cells, normal fibroblasts were more resistant to the cytotoxicity of TRAIL and autophagy inhibitors used either alone or in combination. Notably, TRAIL increased the autophagic flux in the tumor cells, but not in the fibroblasts. Live‑cell imaging revealed that in tumor cells, TRAIL evoked modest mitochondrial fragmentation, while subtoxic concentrations of the autophagy inhibitors led to mitochondrial fusion. Co‑treatment with TRAIL and subtoxic concentrations of the autophagy inhibitors resulted in severe mitochondrial fragmentation, swelling and clustering, similar to what was observed with autophagy inhibitors at toxic concentrations. The enhanced aberration of the mitochondrial network was preceded by a reduction in mitochondrial Ca2+ loading and store‑operated Ca2+ entry. On the whole, the findings of this study indicate that co‑treatment with TRAIL and autophagy inhibitors leads to increased mitochondrial Ca2+ and network dysfunction in a tumor‑selective manner. Therefore, the co‑administration of TRAIL and autophagy inhibitors may prove to be a promising tumor‑targeting approach for the treatment of TRAIL‑resistant cancer cells.

Qu Y, Liao Z, Wang X, et al.
EFLDO sensitizes liver cancer cells to TNFSF10‑induced apoptosis in a p53‑dependent manner.
Mol Med Rep. 2019; 19(5):3799-3806 [PubMed] Related Publications
Ent‑3α‑formylabieta‑8(14),13(15)‑dien‑16,12β‑olide (EFLDO) is a compound extracted from Euphorbia lunulata Bge exhibiting anti‑proliferative activity in vitro. In the present study, EFLDO was identified to sensitize HepG2 cells to tumor necrosis factor (TNF) superfamily member 10 (TNFSF10)‑induced apoptosis. Liver cancer cells were resistant to TNFSF10; however, EFLDO increased TNFSF10‑induced cancer cell viability inhibition and cell apoptosis induction as assessed by MTT assay and Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide assay, respectively. The western blotting results suggested that treatment with EFLDO increased TNFSF10‑induced upregulation of the protein expression levels of pro‑apoptotic proteins, including BCL2 associated agonist of cell death, BCL2 associated X, apoptosis regulator, caspase‑3 (CASP3) and CASP8. Furthermore, treatment with EFLDO increased TNFSF10‑mediated downregulation of the protein expression level of the anti‑apoptotic protein BCL2 apoptosis regulator. Notably, the increase in the activity of CASP3 was consistent with the western blotting results. Treatment with EFLDO sensitized liver cancer cells to TNFSF10, and apoptosis was induced via the upregulation of TNF receptor superfamily member 10a (TNFRSF10A) and TNFRSF10B in a tumor protein p53 (p53)‑dependent manner, as detected by reverse transcription‑quantitative polymerase chain reaction and western blot analyses. In addition, p53 was identified to be necessary for EFLDO‑induced sensitivity to TNFSF10, as assessed by western blotting and Annexin V‑FITC assay. Collectively, the present results suggested a novel mechanism underlying EFLDO function in liver cancer. Treatment with EFLDO was able to increase the antitumor effect of TNFSF10 in liver cancer cells in a p53‑dependent manner.

Scheurer MJJ, Brands RC, El-Mesery M, et al.
The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.

Genov N, Basti A, Abreu M, Relógio A
Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes

van Bastelaar J, Granzier R, van Roozendaal LM, et al.
Analysis of TNF-α and interleukin-6 in seroma of patients undergoing mastectomy with or without flap fixation: is there a predictive value for seroma formation and its sequelae?
Surg Oncol. 2019; 28:36-41 [PubMed] Related Publications
BACKGROUND: Seroma formation is a common complication after mastectomy. Flap fixation has the potential to prevent seroma formation, but identifying patients that are at risk of developing seroma, remains challenging. The aim of this study was to assess the association between pro-inflammatory cytokines in seroma fluid one day after surgery and seroma formation and it sequelae.
METHODS: Patients undergoing mastectomy were randomized into one of three groups: no flap fixation, flap fixation using sutures or flap fixation using tissue glue. Seroma samples from 40 consecutive patients undergoing mastectomy were collected on the first postoperative day for analysis of interleukin-6 and tumor necrosis factor-α. Seroma formation and its sequelae were assessed in the outpatient clinic ten days, six weeks and three months after surgery.
RESULTS: TNF-α concentrations were not detectable in the seroma samples of any of the 40 patients. BMI (p = 0.001) and weight of the resected surgical specimen (p = 0.003) were associated with higher IL-6 levels in seroma on the first postoperative day after mastectomy. A higher seroma concentration of IL-6 was associated with significantly fewer patients with clinical seroma formation three months after surgery (p = 0.027).
CONCLUSION: IL-6 is associated with clinical seroma formation three months after surgery. There is however no evident association between IL-6 and complications related to seroma formation. Higher IL-6 levels are predictive of less long-term seroma formation. Application of flap fixation does not seem to influence the level of IL-6.

Cho HD, Gu IA, Won YS, et al.
Auriculasin sensitizes primary prostate cancer cells to TRAIL-mediated apoptosis through up-regulation of the DR5-dependent pathway.
Food Chem Toxicol. 2019; 126:223-232 [PubMed] Related Publications
Primary prostate cancer cells frequently develop resistance toward chemotherapy as well as most chemotherapeutics have been reported to induce undesirable cytotoxicity in normal cells. In this study, we performed sensitizing activity analysis of auriculasin (AC) to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in RC-58T/h/SA#4 primary prostate cancer cells without significant cytotoxicity in RWPE-1 prostate epithelial cells. Combined treatment with AC and TRAIL at optimal concentrations resulted in tumor-specific apoptotic cell death in RC-58T/h/SA#4 cells, characterized by DNA fragmentation, accumulation of apoptotic cell population, and nuclear condensation. Compared to single treatment with AC or TRAIL, co-treatment with AC and TRAIL significantly increased expression of Bax, cleaved PARP, AIF, endo G, and cytochrome c but decreased expression of phosphorylation of AKT and mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), Bcl-2 and caspases-9, -8, -3, and -10. The sensitizing effect of AC to TRAIL was well correlated with inhibition of death receptor 5 (DR5) CHOP, and p53 expression. Moreover, pre-treatment with a chimeric blocking antibody for DR5 effectively reduced AC-TRAIL-induced cell death and apoptosis-related protein expression. These results suggest that non-toxic concentrations of AC sensitize TRAIL-resistant primary prostate cancer cells to TRAIL-mediated apoptosis via up-regulation of DR5 and downstream signaling pathways.

Liu W, Chen X, He Y, et al.
TNF‑α inhibits xenograft tumor formation by A549 lung cancer cells in nude mice via the HIF‑1α/VASP signaling pathway.
Oncol Rep. 2019; 41(4):2418-2430 [PubMed] Related Publications
Lung cancer is the leading cause of cancer‑associated mortality worldwide. Tumor necrosis factor α (TNF‑α) is an important cytokine in the tumor microenvironment that serves a function in the balance of cell survival and cell death pathways. Our previous studies indicated that hypoxia‑inducible factor 1α (HIF‑1α) acts downstream of TNF‑α in MCF‑7 luminal breast cancer cells. However, whether vasodilator‑stimulated phosphoprotein (VASP) is implicated in the direct regulation of HIF‑1α in response to TNF‑α in lung cancer remains unknown. In vitro studies were performed using A549 and H226 lung carcinoma cells and in vivo studies of tumor xenograft models were performed to investigate the effects of TNF‑α. The results demonstrated that TNF‑α decreased VASP expression by upregulating the expression of HIF‑1α to inhibit A549 cell proliferation and adhesion. Inhibition of transplanted tumor growth was associated with downregulation of VASP expression in nude mice. Bioinformatics analysis indicated that expression levels of VASP or HIF‑1α lead to differential outcomes of overall survival in lung carcinoma. These results suggest that the HIF‑1α/VASP signaling pathway serves an important function in the regulation of TNF‑α‑induced suppression of A549 cell proliferation and xenograft growth. This may improve our understanding of the antitumor effect of TNF‑α.

Xu J, Qian J, Zhang W, et al.
LYPD8 regulates the proliferation and migration of colorectal cancer cells through inhibiting the secretion of IL‑6 and TNF‑α.
Oncol Rep. 2019; 41(4):2389-2395 [PubMed] Related Publications
Ly6/Plaur domain‑containing 8 (LYPD8) contributes to the segregation of intestinal microbiota and intestinal epithelia and is critical for the prevention of intestinal inflammation. However, its relevance in cancer biology remains to be fully elucidated. The present study aimed to clarify the biological effects of LYPD8 on colon cancer tissue from patients and colorectal cancer (CRC) cells. The results revealed that the expression of LYPD8 was significantly reduced in the CRC tissue compared with that in precancerous tissue and normal tissue, particularly in stage III tissue. The results also revealed increased levels of P65 and signal transducer and activator of transcription 3 (STAT3) phosphorylation and increased secretion of interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) in CRC tissue compared with levels in precancerous tissue. Supporting these findings, the levels of secreted TNF‑α and IL‑6 were significantly reduced when LYPD8 was overexpressed in human CRC cells, and the secretion of TNF‑α and IL‑6 were positively associated with the phosphorylation of STAT3 and P65. However, this trend was restored upon supplementation with TNF‑α and IL‑6 in CRC cells. Furthermore, the overexpression of LYPD8 in CRC cells significantly inhibited CRC cell proliferation and migration. Overall, the LYPD8‑mediated tumor‑inhibiting role involves a direct effect on the secretion of IL‑6/TNF‑α in CRC cells by reducing the phosphorylation of STAT3 and P65.

Xian Z, Fu D, Liu S, et al.
Association between B Cell Growth Factors and Primary Sjögren's Syndrome-Related Autoantibodies in Patients with Non-Hodgkin's Lymphoma.
J Immunol Res. 2019; 2019:7627384 [PubMed] Free Access to Full Article Related Publications
Despite the overall success of using R-CHOP for the care for non-Hodgkin's lymphoma patients, it is clear that the disease is quite complex and new insight is needed to further stratify the patient for a better personized treatment. In current study, based on previous studies from animal model, new panels combining well-established cytokine (BAFF) and autoantibodies (anti-SSA/Ro) with newly identified cytokine (IL14) and autoantibodies (TSA) were used to evaluate the association between B cell growth factor and Sjögren's related autoantibodies in NHL patients. The result clearly indicates that there was a unique difference between BAFF and IL14 in association with autoantibodies. While serum BAFF was negatively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in GI lymphoma patient, IL14 was positively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in non-GI lymphoma patient. Long-term follow-ups on these patients and evaluation of their response to the R-CHOP treatment and recurrence rate will be very interesting. Our result provides a solid evidence to support using novel diagnostic panel to better stratify the NHL patients.

Gao H, Niu Z, Zhang Z, et al.
TNFSF15 promoter polymorphisms increase the susceptibility to small cell lung cancer: a case-control study.
BMC Med Genet. 2019; 20(1):29 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Tumor necrosis factor superfamily member 15 (TNFSF15) is closely related to tumorigenesis and development. This study aimed to investigate the correlations between TNFSF15 polymorphisms and genetic susceptibility to lung cancer.
METHODS: This case-control study included 209 small cell lung cancer patients (SCLC), 340 non- small cell lung cancer patients (NSCLC) and 460 health controls. TNFSF15-638 A > G and - 358 T > C polymorphisms were genotyped by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP) analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by unconditional logistic regression.
RESULTS: Our results showed that subjects carrying the TNFSF15-638GG genotype or -358CC genotype were more likely to develop SCLC (-638GG, OR = 1.84, 95%CI = 1.13-2.99; -358CC, OR = 2.44, 95%CI = 1.46-4.06), but not NSCLC (P > 0.05). In stratified analysis, -638GG genotype was related to SCLC among males (OR = 1.95, 95%CI = 1.09-3.45, P = 0.023) and older patients (OR = 2.93, 95%CI = 1.44-8.68, P = 0.006). However, -358CC genotype was associated with SCLC among females (OR = 8.42, 95%CI = 2.22-31.89, P = 0.002) and older subjects with OR (95%CI) of 11.04 (3.57-34.15) (P < 0.001). Moreover, TNFSF15 -358CC was linked with a higher risk of SCLC among non-smokers (OR = 2.54, 95%CI = 1.20-5.35, P = 0.015) but not among smokers (OR = 1.88, 95%CI = 0.92-3.84, P = 0.086).
CONCLUSION: These findings highlight the importance of TNFSF15 polymorphisms in the development of SCLC.

Lee MW, Kim DS, Kim HR, et al.
Inhibition of N-myc expression sensitizes human neuroblastoma IMR-32 cells expressing caspase-8 to TRAIL.
Cell Prolif. 2019; 52(3):e12577 [PubMed] Related Publications
OBJECTIVES: This study aims to explore the roles of N-myc and caspase-8 in TRAIL-resistant IMR-32 cells which exhibit MYCN oncogene amplification and lack caspase-8 expression.
MATERIALS AND METHODS: We established N-myc-downregulated IMR-32 cells using shRNA lentiviral particles targeting N-myc and examined the effect the N-myc inhibition on TRAIL susceptibility in human neuroblastoma IMR-32 cells expressing caspase-8.
RESULTS: Cisplatin treatment in IMR-32 cells increased the expression of death receptor 5 (DR5; TRAIL-R2), but not other receptors, via downregulation of NF-κB activity. However, the cisplatin-mediated increase in DR5 failed to induce cell death following TRAIL treatment. Furthermore, interferon (IFN)-γ pretreatment increased caspase-8 expression in IMR-32 cells, but cisplatin failed to trigger TRAIL cytotoxicity. We downregulated N-myc expression in IMR-32 cells using N-myc-targeting shRNA. These cells showed decreased growth rate and Bcl-2 expression accompanied by a mild collapse in the mitochondrial membrane potential as compared with those treated with scrambled shRNA. TRAIL treatment in N-myc-negative cells expressing caspase-8 following IFN-γ treatment significantly triggered apoptotic cell death. Concurrent treatment with cisplatin enhanced TRAIL-mediated cytotoxicity, which was abrogated by an additional pretreatment with DR5:Fc chimera protein.
CONCLUSIONS: N-myc and caspase-8 expressions are involved in TRAIL susceptibility in IMR-32 cells, and the combination of treatment with cisplatin and TRAIL may serve as a promising strategy for the development of therapeutics against neuroblastoma that is controlled by N-myc and caspase-8 expression.

Xu ZW, Yan SX, Wu HX, et al.
Angiotensin II and tumor necrosis factor-α stimulate the growth, migration and invasion of BEL-7402 cells via down-regulation of GRK2 expression.
Dig Liver Dis. 2019; 51(2):263-274 [PubMed] Related Publications
PURPOSE: To investigate the effects of angiotensin II (Ang II) and tumor necrosis factor-α (TNF-α) on the biological characteristics of hepatocellular carcinoma (HCC) cells and the associated changes in G protein-coupled receptor kinase 2 (GRK2) expression.
METHODS: The mean serum levels of Ang II and TNF-α in normal subjects and patients with benign liver tumors (BLTs) and HCC were evaluated by enzyme-linked immunosorbent assay (ELISA), and liver samples from the patients with HCC and HCC mice were used to assess the protein levels of both cytokines, their major receptors and GRK2. In addition, the dynamics of Bel-7402 cells were determined with cell counting kit-8 (CCK-8) and Transwell experiments, while the levels of the primary cytokine receptors Ang II type-1 receptor (AT1R) and type-2 receptor (AT2R) as well as TNF receptor 1 (TNFR1) were detected by flow cytometry (FCM). The effects of Ang II and TNF-α on the GRK2 levels in Bel-7402 cells and on the dynamics of GRK2-knockdown HCC cells were also investigated.
RESULTS: Both cytokines independently enhanced Bel-7402 cell growth, migration and invasion by decreasing the GRK2 level. In contrast, down-regulating the GRK2 level in Bel-7402 cells suppressed these effects. No synergistic effects were discovered when Ang II and TNF-α were administered together. Furthermore, increased AT1R and TNFR1 levels stimulated HCC initiation and progression, whereas AT2R overexpression produced the opposite effect.
CONCLUSIONS: The present results suggested that Ang II and TNF-α promote Bel-7402 cell growth, migration and invasion by down-regulating GRK2 expression, and that the associated receptors AT1R, AT2R and TNFR1 participate in HCC initiation and progression.

Jaleel JA, Ashraf SM, Rathinasamy K, Pramod K
Carbon dot festooned and surface passivated graphene-reinforced chitosan construct for tumor-targeted delivery of TNF-α gene.
Int J Biol Macromol. 2019; 127:628-636 [PubMed] Related Publications
Gene therapy is a promising alternative that ensures effective treatment and cure for cancer. Here, we report graphene-reinforced chitosan (CS) construct based non-viral vector for tumor-targeted gene therapy. The therapeutic gene, pDNA-TNF-α, was loaded on to chitosan-carboxylated graphene oxide (CS-CGO) construct via electrostatic interaction. The pDNA-TNF-α-CS-CGO thus obtained was further passivated with 4,7,10-trioxa-1,13-tridecanediamine for protecting the vector from the mononuclear phagocyte system that contributes to the prolongation of circulation half-life. The surface passivated carrier (PEG-pDNA-TNF-α-CS-CGO) then festooned with the folic acid derived carbon dots (C-dots) for targeting folate receptors that are overexpressed in most of the cancer cells. The results of TEM images and zeta potential values ensured the occurrence of desired changes in each stage of C-dot-PEG-pDNA-TNF-α-CS-CGO formulation. After 14 days of incubation, the anti-angiogenesis effect was observed for final formulation in the chorioallantoic membrane. The results of in vitro gene expression study in cancer cell line show a comparatively higher transfection efficacy of the developed system (C-dot-PEG-pDNA-TNF-α-CS-CGO) than pDNA-TNF-α. The efficiency of the developed gene delivery system was further confirmed using a developed and validated artificial tumor cell apparatus.

Gundavda MK, Agarwal MG, Reddy R, et al.
Is vitamin D deficiency behind the scenes for high incidence of Giant cell tumor amongst the Indian population? Unraveling the vitamin D - RANKL association.
Med Hypotheses. 2019; 123:67-71 [PubMed] Related Publications
INTRODUCTION: The major neoplastic and proliferative component of GCTB is the stromal tumor cells; that they have shown no evidence of bone destruction, instead the massive tissue destruction appears to be a result of tumor induced osteoclastogenesis. The discovery of receptor activator of nuclear factor kB (RANK) and RANK binding ligand (RANKL) uncovered the bone homeostasis and molecular mechanism by which multiple compounds (including vitamin D) regulated osteoclast differentiation; a function mediated by osteoblastic cells and osteoclast-precursor cells.
HYPOTHESIS: In a country burdened by vitamin D deficiency, causal relation between hypovitaminosis D and GCTB was hypothesized based on the vitamin D mediated RANKL expression and osteoclastogenesis, as India is also a population with higher incidence of GCTB as compared to Western populations described in the literature. The possibility of vitamin D regulated osteoclastogenesis in GCTB is postulated on the evidence from molecular research linking it to the RANK/RANKL/OPG pathway. The aim of this study was to analyse the prevalence of Vitamin D deficiency in patients with primary GCTB and to elucidate any difference in serum Vitamin 25(OD)D
MATERIALS AND RESULTS: 130 patients of primary GCTBs were matched to 310 controls from the general health check population and serum levels of 25(OH)D
DISCUSSION: The differential expression of RANKL and OPG in response to levels of vitamin D has been established. The stromal cells of osteolytic GCTB express high levels of RANKL, which is a key signal regulator in development of this disease and bone destruction typical of GCTBs. This has resulted in research targeting this pathway for therapeutic approach in GCTBs. As vitamin D supplementation is simple and safe, increased awareness to assess and if necessary correct vitamin D status of patients is warranted, however the question as to whether patients with low vitamin D levels are more prone to develop GCTB and thus would profit from vitamin D supplementation remains unanswered. To conclude, it is essential to assess vitamin D levels in patients with GCTB as deficiency is pronounced. Future research on this hypothesis might lead to an association between Vitamin D deficiency and the onset/natural history of GCTB that may in the future help us cure or prevent GCTBs.

Kim YH, Shin EA, Jung JH, et al.
Galbanic acid potentiates TRAIL induced apoptosis in resistant non-small cell lung cancer cells via inhibition of MDR1 and activation of caspases and DR5.
Eur J Pharmacol. 2019; 847:91-96 [PubMed] Related Publications
Galbanic acid (GBA) is known a sesquiterpene coumarin to have apoptotic, anti-hypoxic, anti-proliferative, anti-hepatitis, anti-angiogenic, anti-bacteria and anti-thrombotic effects. Also, antitumor effect of GBA was reported in prostate, ovary, breast and lung cancers. Nevertheless, the underlying molecular mechanism of GBA was not fully understood to overcome chemoresistance in resistant lung cancer so far. Thus, synergistic antitumor mechanism of GBA and TNF-related apoptosis-inducing ligand (TRAIL) was elucidated in H460 and resistant H460/R non-small cell lung cancer cells (NSCLCs). Combination of GBA and TRAIL significantly exerted cytotoxicity in a dose dependent manner compared to GBA or TRAIL alone in H460/R cells. Also, GBA and TRAIL significantly increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and sub-G1 population in a dose dependent manner in H460/R cells. Consistently, GBA and TRAIL induced cleavages of poly (ADP-ribose) polymerase (PARP), caspase-9 and caspase-8 along with upregulation of death receptor 5 (DR5) and also attenuated the expression of B-cell lymphoma-extra-large (Bcl-x

van Dam PA, Verhoeven Y, Trinh XB, et al.
RANK/RANKL signaling inhibition may improve the effectiveness of checkpoint blockade in cancer treatment.
Crit Rev Oncol Hematol. 2019; 133:85-91 [PubMed] Related Publications
Binding between the receptor activator of nuclear factor-kB (RANK) and its ligand (RANKL) triggers recruitment of TNF receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG) which interacts with RANKL. Additional networks regulating RANK/RANKL signaling are active in a context specific manner. RANK/RANKL signaling is essential for the differentiation of bone-resorbing osteoclasts, and is deregulated in pathological processes such as postmenopausal osteoporosis or cancer induced bone destruction. Cells expressing RANK and RANKL are commonly found in the tumor microenvironment. The RANKL/RANK pathway is often overexpressed in tumors of the breast, prostate, endometrium, cervix, stomach, oesophagus and bladder, thyroid and correlated with poor prognosis. RANK signaling plays an important role in the innate and adaptive immune response as it generates regulatory T (Treg) cells and increases production of cytokines. RANK expression induces chemoresistance in vitro through the activation of multiple signal transduction pathways. RANKL blockade improves the efficacy of anti-CTLA-4 monoclonal antibodies against solid tumors and experimental metastases. As RANK inhibition enhances the immune response there is an increasing interest in combining it with immune therapy in an attempt to sensitize immune resistant tumors to immune therapies. Several studies are ongoing to assess this concept. The role of RANK/RANKL inhibition should be further pursued as an immunomodulatory strategy in combination with other treatment modalities.

Gadalla R, Hassan H, Ibrahim SA, et al.
Tumor microenvironmental plasmacytoid dendritic cells contribute to breast cancer lymph node metastasis via CXCR4/SDF-1 axis.
Breast Cancer Res Treat. 2019; 174(3):679-691 [PubMed] Related Publications
PURPOSE: Plasmacytoid dendritic cells (PDCs) infiltration into breast cancer tissues is associated with poor prognosis. Also, CXCR4 shows compelling evidences to be exploited by cancer cells to migrate to distant sites. The present study investigated lymph node metastasis in the light of PDCs infiltration and the potential cross talk with CXCR4/SDF-1 chemokine axis.
METHODS: We assessed circulating PDCs proportions drained from the axillary tributaries, and the in situ expression of both CD303 and CXCR4 in breast cancer patients with positive lymph nodes (pLN) and negative lymph nodes (nLN) using immunohistochemistry and flow cytometry. We also analyzed the expression of SDF-1 in lymph nodes of pLN and nLN patients. We studied the effect of the secretome of PDCs of pLN and nLN patients on the expression of CXCR4 and activation of NF-κB in human breast cancer cell lines SKBR3 and MCF-7. TNF-α mRNA expression level in PDCs from both groups was determined by qPCR.
RESULTS: Our findings indicate increased infiltration of PDCs in breast cancer tissues of pLN patients than nLN patients, which correlates with CXCR4
CONCLUSIONS: Our findings suggest a potential role for microenvironmental PDCs in breast cancer lymph node metastasis via CXCR4/SDF-1 axis.

Ding S, Ma H, Wang G, et al.
Effect of Remifentanil Combined Anesthesia on Cytokines and Oxidative Stress in Patients undergoing Laparoscopic Surgery for Colon Cancer.
J Coll Physicians Surg Pak. 2019; 29(1):8-11 [PubMed] Related Publications
OBJECTIVE: To investigate the effect of remifentanil combined anesthesia on serum cytokines and oxidative stress indices in patients undergoing laparoscopic surgery for colon cancer.
STUDY DESIGN: Experimental study.
PLACE AND DURATION OF STUDY: Department of Anesthesiology, Yuhuangding Hospital Affiliated to Qingdao University, Yantai, China, from May 2016 to March 2018.
METHODOLOGY: A total of 154 patients undergoing laparoscopic surgery for colon cancer were randomly divided into control group and observation group, with 77 cases in each group. Control group received fentanyl combined anesthesia, and observation group received remifentanil combined anesthesia. Levels of serum cytokines IL-8, IL-6, CRP, TNF- α and the levels of oxidative stress indices SOD, MDA, CAT, and GSH on the first day after operation were compared. Occurrence of adverse reactions during anesthesia recovery was observed and recorded in both groups.
RESULTS: On the first day after surgery, levels of serum cytokines IL-8, IL-6, CRP, TNF- α and MDA in the observation group were lower than those in the control group (all p<0.001); levels of serum SOD, GSH, and CAT in the observation group were higher than those in the control group (all p<0.001). The frequency of adverse reactions such as nausea and vomiting, chills, restlessness, cough, and tachycardia in the observation group was lower than that in the control group (p=0.029, 0.016, 0.009, 0.025, and 0.003, respectively).
CONCLUSION: Compared with fentanyl combined anesthesia, the remifentanil combined anesthesia can significantly reduce serum levels of cytokines IL-8, IL-6, CRP, TNF- α and oxidative stress level, and is, therefore, more secure for patients undergoing laparoscopic surgery for colon cancer.

Jia Q, Tian F, Duan WN, et al.
Effects of Dezocine-Remifentanil Intravenous Anaesthesia on Perioperative Signs, Serum TNF-&aipha; and IL-6 in Liver Cancer Patients undergoing Radiofrequency Ablation.
J Coll Physicians Surg Pak. 2019; 29(1):4-7 [PubMed] Related Publications
OBJECTIVE: To analyse the impact of dezocine-remifentanil intravenous anaesthesia on perioperative signs, serum tumour necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in liver cancer patients undergoing radiofrequency ablation (RFA).
STUDY DESIGN: An experimental study.
PLACE AND DURATION OF STUDY: Renmin Hospital of Wuhan University, Wuhan, China, from January 2017 to February 2018.
METHODOLOGY: Eighty patients with small hepatocellular carcinoma (SHCC) were selected as the research object. They were divided into Group A and Group B with the random number table method, with 40 cases in each group. Group A were given dezocine-remifentanil intravenous anaesthesia and Group B were given midazolam-remifentanil intravenous anaesthesia. Patients' situations in the surgery were compared between the two groups. Changes in heart rate (HR), mean arterial pressure (MAP) and blood oxygen saturation (SpO2) were recorded before the surgery (T0), at 5 minutes after the RFA (T1) and at the end of the RFA (T2). Levels of tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) on the 12 day after the RFA were compared between the two groups.
RESULTS: The wake-up time in Group A was shorter than Group B (p<0.001), and the VAS pain score in Group A was lower than Group B (p<0.001). At T1, the MAP in Group A was higher than Group B (p<0.001). There was no significant difference in MAP between the two groups at T0 and T2 (p=0.881, 0.696, respectively). At T1 and T2, the HR in Group A was lower than Group B (all p<0.001). There was no significant difference in HR between the two groups at T0 (p=0.684). There was no significant difference in SpO2 between the two groups at T0, T1 and T2 (p=0.654, 0.884 and 0.798, respectively). On the 1st day after the RFA, the level of TNF-α, IL-6 in Group A were lower than those of Group B (all p<0.001). There was no significant difference in the incidence of intraoperative complications between the two groups (p=0.644).
CONCLUSION: Compared with midazolam-remifentanil intravenous anaesthesia, the dezocine-remifentanil method has a better analgesic effect, shorter wake-up time, and can effectively regulate the expression of inflammatory cytokines TNF-α and IL-6. However, the effect of remifentanil on the respiratory function is dose-dependent. Therefore, respiratory cycle monitoring and management should be strengthened during the surgery.

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