|, APO2L, Apo-2L, CD253, TL2, TRAIL, TNLG6A, tumor necrosis factor superfamily member 10, TNF superfamily member 10|
TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells, by binding to certain death receptors. TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, as of 2013, these have not shown significant survival benefit. TRAIL has also been implicated as a pathogenic or protective factor in various pulmonary diseases, particularly pulmonary arterial hypertension.
In humans, the gene that encodes TRAIL is located at chromosome 3q26, which is not close to other TNF family members. The genomic structure of the TRAIL gene spans approximately 20 kb and is composed of five exonic segments 222, 138, 42, 106, and 1245 nucleotides and four introns of approximately 8.2, 3.2, 2.3 and 2.3 kb.
The TRAIL gene lacks TATA and CAAT boxes and the promoter region contains putative response elements for transcription factors GATA, AP-1, C/EBP, SP-1, OCT-1, AP3, PEA3, CF-1, and ISRE.
The TRAIL gene as a drug targetEdit
TRAIL shows homology to other members of the tumor necrosis factor superfamily. It is composed of 281 amino acids and has characteristics of a type II transmembrane protein. The N-terminal cytoplasmic domain is not conserved across family members, however, the C-terminal extracellular domain is conserved and can be proteolytically cleaved from the cell surface. TRAIL forms a homotrimer that binds three receptor molecules.
TRAIL binds to the death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII). The process of apoptosis is caspase-8-dependent. Caspase-8 activates downstream effector caspases including procaspase-3, -6, and -7, leading to activation of specific kinases. TRAIL also binds the receptors DcR1 and DcR2, which do not contain a cytoplasmic domain (DcR1) or contain a truncated death domain (DcR2). DcR1 functions as a TRAIL-neutralizing decoy-receptor. The cytoplasmic domain of DcR2 is functional and activates NFkappaB. In cells expressing DcR2, TRAIL binding therefore activates NFkappaB, leading to transcription of genes known to antagonize the death signaling pathway and/or to promote inflammation. Application of engineered ligands that have variable affinity for different death (DR4 and DR5) and decoy receptors (DCR1 and DCR2) may allow selective targeting of cancer cells by controlling activation of Type 1/Type 2 pathways of cell death and single cell fluctuations. Luminescent iridium complex-peptide hybrids, which mimic TRAIL, have recently been synthesized in vitro. These artificial TRAIL mimics bind to DR4/DR5 on cancer cells and induce cell death via both apoptosis and necrosis, which makes them a potential candidate for anticancer drug development.
The TRAIL receptors as a drug targetEdit
In clinical trials only a small proportion of cancer patients responded to various drugs that targeted TRAIL death receptors. Many cancer cell lines develop resistance to TRAIL and limits the efficacy of TRAIL-based therapies.
- GRCh38: Ensembl release 89: ENSG00000121858 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000039304 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA (December 1995). "Identification and characterization of a new member of the TNF family that induces apoptosis". Immunity. 3 (6): 673–82. doi:10.1016/1074-7613(95)90057-8. PMID 8777713.
- Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A (May 1996). "Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family". The Journal of Biological Chemistry. 271 (22): 12687–90. doi:10.1074/jbc.271.22.12687. PMID 8663110.
- "TNFSF10". NCBI Gene.
- Cormier Z (February 2013). "Small-molecule drug drives cancer cells to suicide". Nature. 494. doi:10.1038/nature.2013.12385.
- Braithwaite AT, Marriott HM, Lawrie A (2018). "Divergent Roles for TRAIL in Lung Diseases". Frontiers in Medicine. 5: 212. doi:10.3389/fmed.2018.00212. PMC 6072839. PMID 30101145.
- ONC201: Stressing tumors to death. Feb 2016
- Song JJ, Lee YJ (May 2008). "Differential cleavage of Mst1 by caspase-7/-3 is responsible for TRAIL-induced activation of the MAPK superfamily". Cellular Signalling. 20 (5): 892–906. doi:10.1016/j.cellsig.2008.01.001. PMC 2483832. PMID 18276109.
- Masum AA, Yokoi K, Hisamatsu Y, Naito K, Shashni B, Aoki S (September 2018). "Design and synthesis of a luminescent iridium complex-peptide hybrid (IPH) that detects cancer cells and induces their apoptosis". Bioorganic & Medicinal Chemistry. 26 (17): 4804–4816. doi:10.1016/j.bmc.2018.08.016. PMID 30177492.
- Masum AA, Hisamatsu Y, Yokoi K, Aoki S (2018-08-01). "Luminescent Iridium Complex-Peptide Hybrids (IPHs) for Therapeutics of Cancer: Design and Synthesis of IPHs for Detection of Cancer Cells and Induction of Their Necrosis-Type Cell Death". Bioinorganic Chemistry and Applications. 2018: 7578965. doi:10.1155/2018/7578965. PMC 6092981. PMID 30154833.
- Dimberg LY, Anderson CK, Camidge R, Behbakht K, Thorburn A, Ford HL (March 2013). "On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics". Oncogene. 32 (11): 1341–50. doi:10.1038/onc.2012.164. PMC 4502956. PMID 22580613.
- Kaptein A, Jansen M, Dilaver G, Kitson J, Dash L, Wang E, Owen MJ, Bodmer JL, Tschopp J, Farrow SN (November 2000). "Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3)". FEBS Letters. 485 (2–3): 135–41. doi:10.1016/S0014-5793(00)02219-5. PMID 11094155.
- Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT (September 1997). "TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL". The EMBO Journal. 16 (17): 5386–97. doi:10.1093/emboj/16.17.5386. PMC 1170170. PMID 9311998.
- Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A, de Vos AM (October 1999). "Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5". Molecular Cell. 4 (4): 563–71. doi:10.1016/S1097-2765(00)80207-5. PMID 10549288.
- Almasan A, Ashkenazi A (2004). "Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy". Cytokine & Growth Factor Reviews. 14 (3–4): 337–48. doi:10.1016/S1359-6101(03)00029-7. PMID 12787570.
- Cha SS, Song YL, Oh BH (2004). "Specificity of molecular recognition learned from the crystal structures of TRAIL and the TRAIL:sDR5 complex". Vitamins & Hormones. 67: 1–17. doi:10.1016/S0083-6729(04)67001-4. ISBN 978-0-12-709867-8. PMID 15110168. Cite journal requires
- Song C, Jin B (2005). "TRAIL (CD253), a new member of the TNF superfamily". Journal of Biological Regulators and Homeostatic Agents. 19 (1–2): 73–7. PMID 16178278.
- Bucur O, Ray S, Bucur MC, Almasan A (May 2006). "APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy". Frontiers in Bioscience. 11: 1549–68. doi:10.2741/1903. PMID 16368536.