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Insulin promotes vascular smooth muscle cell proliferation and apoptosis via differential regulation of tumor necrosis factor-related apoptosis-inducing ligand

Harith HH, Di Bartolo BA, Cartland SP, Genner S, Kavurma MM

J Diabetes, 2016 Jul;8(4):568-78.
PMID: 26333348 DOI: 10.1111/1753-0407.12339

BACKGROUND: Insulin regulates glucose homeostasis but can also promote vascular smooth muscle (VSMC) proliferation, important in atherogenesis. Recently, we showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) stimulates intimal thickening via accelerated growth of VSMCs. The aim of the present study was to determine whether insulin-induced effects on VSMCs occur via TRAIL.
METHODS: Expression of TRAIL and TRAIL receptor in response to insulin and glucose was determined by polymerase chain reaction. Transcriptional activity was assessed using wild-type and site-specific mutations of the TRAIL promoter. Chromatin immunoprecipitation studies were performed. VSMC proliferation and apoptosis was measured.
RESULTS: Insulin and glucose exposure to VSMC for 24 h stimulated TRAIL mRNA expression. This was also evident at the transcriptional level. Both insulin- and glucose-inducible TRAIL transcriptional activity was blocked by dominant-negative specificity protein-1 (Sp1) overexpression. There are five functional Sp1-binding elements (Sp1-1, Sp1-2, Sp-5/6 and Sp1-7) on the TRAIL promoter. Insulin required the Sp1-1 and Sp1-2 sites, but glucose needed all Sp1-binding sites to induce transcription. Furthermore, insulin (but not glucose) was able to promote VSMC proliferation over time, associated with increased decoy receptor-2 (DcR2) expression. In contrast, chronic 5-day exposure of VSMC to 1 µg/mL insulin repressed TRAIL and DcR2 expression, and reduced Sp1 enrichment on the TRAIL promoter. This was associated with increased cell death.
CONCLUSIONS: The findings of the present study provide a new mechanistic insight into how TRAIL is regulated by insulin. This may have significant implications at different stages of diabetes-associated cardiovascular disease. Thus, TRAIL may offer a novel therapeutic solution to combat insulin-induced vascular pathologies.

Matched MeSH terms: Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
Activation of death receptor, DR5 and mitochondria-mediated apoptosis by a 3,4,5-trimethoxybenzyloxy derivative in wild-type and p53 mutant colorectal cancer cell lines

Chan ZCK, Leong KH, Kareem HS, Norazit A, Noor SM, Ariffin A

Naunyn Schmiedebergs Arch Pharmacol, 2020 03;393(3):405-417.
PMID: 31641820 DOI: 10.1007/s00210-019-01730-2

The rationale of designing compounds containing a (3,4,5-trimethoxybenzyloxy) phenyl moiety is largely due to its potential antioxidant and cytotoxic activities. A previous study focused on its antioxidant mechanism, whereas in this study, we investigated the cytotoxicity of a series of 28 analogues and the mechanism of apoptosis of the most cytotoxic compound against wild-type (HCT-116) and p53 mutant (HT-29) colorectal cancer cell lines. The series of analogues comprise of different families, namely hydrazone, oxadiazole, thiosemicarbazides and triazoles. In the initial cytotoxicity screening, N-(3,4,5-trimethoxybenzylidene)-4-(3,4,5-trimethoxybenzyloxy) benzohydrazide, henceforth known as, P5H, was found to be most cytotoxic against human colorectal cancer cell lines (IC50 for HCT-116 = 11.79 μM and HT-29 = 18.52 μM). Additionally, P5H was found to have some degree of selectivity towards cancer cells compared to normal human colon cells (CCD-112 CoN). Subsequent investigation had brought insight on P5H ability to induce apoptosis in both HCT-116 and HT-29 cell lines. Cell cycle analysis showed both cell lines were arrested at the G2/M phase upon treatment. Our study concluded that P5H induced the death receptor, DR5 in HCT-116 and mitochondria-mediated apoptosis pathway in HT-29. Therefore, P5H may be a promising candidate as a chemotherapy agent against colon cancer. Graphical abstract The apoptotic pathways induced in HT-29 and HCT-116 cells upon P5H treatment.

Matched MeSH terms: Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism*
The TRAIL to cancer therapy: Hindrances and potential solutions

Wong SHM, Kong WY, Fang CM, Loh HS, Chuah LH, Abdullah S, et al.

Crit Rev Oncol Hematol, 2019 Nov;143:81-94.
PMID: 31561055 DOI: 10.1016/j.critrevonc.2019.08.008

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings.

Matched MeSH terms: Receptors, TNF-Related Apoptosis-Inducing Ligand/agonists*
Fulltext Molecular responses during chemotherapy in acute myeloid leukemias in predicting poor-response to standard chemotherapy

Maha A, Cheong SK, Leong CF, Seow HF

Malays J Pathol, 2009 Dec;31(2):81-91.
PMID: 20514850 MyJurnal

Signal transduction pathways are constitutively expressed in leukaemic cells resulting in aberrant survival of the cells. It is postulated that in cells of chemo-sensitive patients, chemotherapy induces apoptotic signals leading to cell death while survival signals are maintained in cells of chemo-resistant patients. There is very little information currently, on the expression of these mediators in patients immediately after chemotherapy initiation. We examined the expression pattern of proinflammatory cytokines, signaling molecules of the PI3K and MAPK pathways molecules and death receptor, DR5 on paired samples at diagnosis and during chemotherapy in acute myeloid leukaemia patients treated with cytosine arabinoside and daunorubicin. The results were correlated with remission status one month after chemotherapy. We found that in chemo-sensitive patients, chemotherapy significantly increased the percentage of cases expressing TNF-alpha (p = 0.025, n = 9) and IL-6 (p = 0.002, n = 11) compared to chemo-resistant cases. We also observed an increased percentage of chemo-sensitive cases expressing DR5 and phosphorylated p38, and Jnk. Thus, expression of TNF-alpha, IL-6, DR5, phospho-p38 and phospho-Jnk may regulate cell death in chemo-sensitive cases. In contrast, a significantly higher percentage of chemo-resistant cases expressed phospho-Bad (p = 0.027, n = 9). IL-beta and IL-18 were also found to be higher in chemo-resistant cases at diagnosis and during chemotherapy. Thus, expression of various cellular molecules in leukaemic blasts during chemotherapy may be useful in predicting treatment outcome. These cellular molecules may also be potential targets for alternative therapy.

Matched MeSH terms: Receptors, TNF-Related Apoptosis-Inducing Ligand/drug effects; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism
Fulltext Effect of cigarette smoke exposure to expression of TRAIL R1 on tongue epithelium Rattus Novergicus

Herlambang Devianto, Desiana Radithia, Bagus Soebadi, Adiastuti Endah Parmadiati, Rosnah Zain

Malaysian Journal of Medicine and Health Sciences, 2019;15(107):36-36.
MyJurnal

Introduction: One of the risk factors for cancer is the habit of smoking. Some carcinogenic substances in ciga-rettes are nicotine and nitrosamine. In cigarette smoke there are free radical molecules or Reactive Oxygen Species (ROS) that can cause DNA mutations that can disrupt the balance of cell metabolism. One of them is the apoptosis, apoptosis is a programmed cell death mechanism. In cancer conditions there are apoptotic disorders and excessive proliferation of cells. The process of apoptosis is influenced by the death receptor, Tumor Necrosis Factor apoptosis inducing ligand R1 (TRAIL R1). This study aims to determine the effect of smoke exposure to expression of TRAIL R1 on the mucosal epithelium of the tongue of the Wistar rat (Rattus Novergicus). Methods: The subjects of this study were 24 male Rattus Novergicus with the age range of 12-14 weeks and weighing ± 170 grams. Divided into 4 groups with 2 control groups 4 weeks (K4), 8 weeks (K8) and 2 treatment groups each given 2 cigarettes / day ex-posure to cigarette smoke for each rat for 4 weeks (P4) and 8 weeks (P8). Results: The results showed that exposure to cigarette smoke can cause interference with TRAIL R1 expression. There was a significant difference in TRAIL R1 expression between the control and treatment groups and there was a significant difference in TRAIL R1 expression between the duration of cigarette smoke exposure (P4 and P8). Conclusion: Exposure to cigarette smoke can interfere with the process of apoptosis.

Matched MeSH terms: Receptors, TNF-Related Apoptosis-Inducing Ligand
Fulltext Targeting of CD133+ Cancer Stem Cells by Mesenchymal Stem Cell Expressing TRAIL Reveals a Prospective Role of Apoptotic Gene Regulation in Non-Small Cell Lung Cancer

Fakiruddin KS, Lim MN, Nordin N, Rosli R, Zakaria Z, Abdullah S

Cancers (Basel), 2019 08 28;11(9).
PMID: 31466290 DOI: 10.3390/cancers11091261

Mesenchymal stem cells (MSCs) are emerging as vehicles for anti-tumor cytotherapy; however, investigation on its efficacy to target a specific cancer stem cell (CSC) population in non-small cell lung cancer (NSCLC) is lacking. Using assays to evaluate cell proliferation, apoptosis, and gene expression, we investigated the efficacy of MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) to target and destroy CD133+ (prominin-1 positive) NSCLC-derived CSCs. Characterization of TRAIL death receptor 5 (DR5) revealed that it was highly expressed in the CD133+ CSCs of both H460 and H2170 cell lines. The human MSC-TRAIL generated in the study maintained its multipotent characteristics, and caused significant tumor cell inhibition in NSCLC-derived CSCs in a co-culture. The MSC-TRAIL induced an increase in annexin V expression, an indicator of apoptosis in H460 and H2170 derived CD133+ CSCs. Through investigation of mitochondria membrane potential, we found that MSC-TRAIL was capable of inducing intrinsic apoptosis to the CSCs. Using pathway-specific gene expression profiling, we uncovered candidate genes such as NFKB1, BAG3, MCL1, GADD45A, and HRK in CD133+ CSCs, which, if targeted, might increase the sensitivity of NSCLC to MSC-TRAIL-mediated inhibition. As such, our findings add credibility to the utilization of MSC-TRAIL for the treatment of NSCLC through targeting of CD133+ CSCs.

Matched MeSH terms: Receptors, TNF-Related Apoptosis-Inducing Ligand
A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells

Dyari HRE, Rawling T, Chen Y, Sudarmana W, Bourget K, Dwyer JM, et al.

FASEB J, 2017 12;31(12):5246-5257.
PMID: 28798154 DOI: 10.1096/fj.201700033R

A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor-associated factor 2, but not Fas-associated death domain, prevented C20E-mediated apoptosis. B-cell lymphoma-2 homology 3-interacting domain death agonist (Bid) cleavage by JNK/p38 MAPK linked the extrinsic and mitochondrial pathways of apoptosis. In further studies, an antibody against the extracellular domain of TNFR1 prevented apoptosis by TNF-α but not C20E. These findings suggest that C20E acts intracellularly at TNFR1 to activate ASK1-MKK4/7-JNK/p38 MAPK signaling and to promote Bid-dependent mitochondrial disruption and apoptosis. Inin vivostudies, tumors isolated from C20E-treated nu/nu mice carrying MDA-MB-231 xenografts showed increased TUNEL staining and decreased Ki67 staining, reflecting increased apoptosis and decreased proliferation, respectively. ω-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells.

Matched MeSH terms: Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism