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The Use of Fusicoccin as Anticancer Compound
Published in Zulkhair A. Mansurov, Carbon Nanomaterials in Biomedicine and the Environment, 2020
Seitkhan Azat, Almagul R. Kerimkulova, Zulkhair A. Mansurov, Sergazy Adekenov, Gerhard Artmann
There are two major pathways known for apoptosis induction. The extrinsic pathway that starts on the cell surface by death receptor (DR) activation, and the intrinsic pathway that involves the activation of mitochondria followed by cytochrome c release [4, 5]. The activation of both pathways results directly or indirectly in the activation of the caspase cascade followed by the execution of apoptosis. Ideally, an apoptosis-inducing therapy affects only cancer cells without harming healthy cells. One ligand known to be relatively tumor specific is TNF-related apoptosis inducing ligand (TRAIL) [4, 6, 7]. TRAIL can induce apoptosis by the interaction with two closely related death receptors, DR4 and DR5, which activate the caspase cascade. TRAIL also interacts with decoy receptors (DcRs), DcR1 and DcR2. These receptors lack the intracellular domain completely or partially and are therefore not able to transduce the apoptotic signal. The difference in the expression ratio between DRs and DcRs in cancer versus healthy cells and the difference in their TRAIL-affinity is suggested to account for the tumor specificity of TRAIL [4, 7, 8].
Terpenoids: The Biological Key Molecules
Published in Dijendra Nath Roy, Terpenoids Against Human Diseases, 2019
Moumita Majumdar, Dijendra Nath Roy
Apoptosis or type-1 programmed cell death is initiated by the activation of death receptor (DR) signalling through the binding of the Fas receptor (FasR), TNF receptor (TNFR), DR3, DR4 and DR5 with their respective ligands, resulting in conformational change. After oligomerisation of the receptor via ligands, specialized adaptor proteins activate the caspase cascades. Trimerisation of Fas by binding with FasI recruits adaptor protein Fas-associated death domain (FADD), which activates caspase-8. After oligomerisation, caspase-8 initiates the signalling that stimulates apoptosis via two parallel pathways. In the absence of the caspase cascade, death receptors activate another alternative signalling system designated as necroptosis via formation of the IIb complex. As the largest group of natural products, plant terpenoids have a promising effect on death domain signalling.
Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Lixin Zheng, Richard M. Siegel, Jagan R. Muppidi, Felicita Hornung, Michael J. Lenardo
The TNF/TNFR superfamilies are large groups of proteins that act as ligand/receptor-interacting molecules. It is well known that most of the ligand members of this family are type-II transmembrane proteins that are expressed as trimers on the cell surface or shed from the cell surface as cytokines. Many of the receptor members are type-I transmembrane proteins with 2-6 extracellular cysteine-rich domains and cytoplasmic signaling tails. TNFR family members have pleiotropic functions depending on cell type and status, as well as the availability of other signals. A subfamily of TNFR superfamily has been classified as “death receptors” based on their sharing of a homologous cytoplasmic “death domain” (DD). There are at least 8 pairs of ligands/receptors in this subfamily. The receptor members of this subfamily include CD95 (Fas), TNFR1, death receptor 3 (DR3),93 DR4 (TRAIL receptorl, TR1),94 DR5 (TRAIL receptor 2,TR2),64 DR6,65 NGFRp75 and CARI,95 each containing a homologous cytoplasmic death domain that is essential for apoptosis induction.58,96-98 These DD-containingTNFR family members are thus often referred to as death receptors and their corresponding ligands are recognized as death ligands, although it is uncertain if death is the primary function of all these molecules. Some characteristics of death receptors and their associated proteins are summarized in Table 1 and Table 2. It was believed that death-ligand trimers could recruit and trimerize individual death receptors triggering apoptosis.99 However, recent data suggests that CD95, TNFR1, and TNFR2 pre-assemble as dimers or trimers through their extracellular “pre-ligand assembling domain” (PLAD) before ligand occupancy. The pre-assembled CD95 and TNFR oligomers appear to be essential for CD95L/CD95 and TNF/TNFR interactions as well as signaling for apoptosis.100,101 These findings support the hypothesis that pre-ligand assembly might be a general feature of the TNFR superfamily. They also shed light on strategies for developing new drugs that block the interactions between death ligands and their receptors to modulate programmed cell death as well as other TNFR-signaling-related disorders.
Cytochrome P450 1B1 promotes cancer cell survival via specificity protein 1 (Sp1)-mediated suppression of death receptor 4
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Yeo-Jung Kwon, Nam-Hyeon Cho, Dong-Jin Ye, Hyoung-Seok Baek, Yeon-Sang Ryu, Young-Jin Chun
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo2L, is a multifunctional cytokine released from natural killer immune cells (Schaefer et al. 2007; Smyth et al. 2005). Since its identification, the potential of TRAIL as an anticancer therapeutic agent has been widely examined because of its tumor-specific induction of apoptosis (Walczak et al. 1999). The basis for preferential cytotoxicity of TRAIL in cancer cells over normal cells is still not fully understood. However, there are several reports that the two decoy receptors for TRAIL (TRAIL-R3 and TRAIL-R4) are exclusively expressed in normal cells, whereas cancer cells usually express only death receptors (DRs) 4 and 5 (Ashkenazi 2002; Kelley and Ashkenazi 2004; Zhang et al. 2000). The decoy receptors in normal cells act as competitive antagonists against DR for TRAIL binding and subsequently protect normal cells from TRAIL-induced cytotoxic effects (Ashkenazi 2002; Kelley and Ashkenazi 2004; Zhang et al. 2000). Despite the potential significant merit of TRAIL as an anticancer therapeutic, its clinical use is limited due to the acquired resistance of cancer cells to TRAIL, including mutations on DR for TRAIL (TRAIL-R1/DR4 and TRAIL-R2/DR5) (Ozoren and El-Deiry 2003). To overcome the resistance, cooperative therapeutic methods for TRAIL-induced cancer cell apoptosis, such as (1) co-treatment with TRAIL and agonistic antibodies for DR4/5 or (2) using a nanocarrier for TRAIL delivery to tumors, are currently under development (Johnstone, Frew, and Smyth 2008; Micheau, Shirley, and Dufour 2013).