Limits...
Marine Drugs Regulating Apoptosis Induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL).

Elmallah MI, Micheau O - Mar Drugs (2015)

Bottom Line: Marine biomass diversity is a tremendous source of potential anticancer compounds.Its selectivity for cancer cells has attracted much attention in oncology.This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, Helwan University, Ain Helwan, Cairo 11790, Egypt. mohamed_almallah@science.helwan.edu.eg.

ABSTRACT
Marine biomass diversity is a tremendous source of potential anticancer compounds. Several natural marine products have been described to restore tumor cell sensitivity to TNF-related apoptosis inducing ligand (TRAIL)-induced cell death. TRAIL is involved during tumor immune surveillance. Its selectivity for cancer cells has attracted much attention in oncology. This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

Show MeSH

Related in: MedlinePlus

Schematic representation of TRAIL pro-apoptotic proximal signaling regulation. Apoptosis induced by TRAIL is initiated through homo/or hetero-oligomerization of DR4 and/or DR5 and subsequent chain assembly of initiator caspases (1). Proximal activation of caspase-8 by these receptors can be inhibited by TRAIL antagonistic receptors DcR2 (2), DcR1, and OPG (3), as well as by the cellular caspase-8 inhibitor, c-FLIP (4) (see text for explanations).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4663558&req=5

marinedrugs-13-06884-f002: Schematic representation of TRAIL pro-apoptotic proximal signaling regulation. Apoptosis induced by TRAIL is initiated through homo/or hetero-oligomerization of DR4 and/or DR5 and subsequent chain assembly of initiator caspases (1). Proximal activation of caspase-8 by these receptors can be inhibited by TRAIL antagonistic receptors DcR2 (2), DcR1, and OPG (3), as well as by the cellular caspase-8 inhibitor, c-FLIP (4) (see text for explanations).

Mentions: Efficient activation of initiator caspases, upon TRAIL stimulation, is tightly dependent on the quality of the DISC, determining the strength of activation of the initiator caspases [24]. Irrespective of whether the apoptotic signal is transduced by DR4 or DR5, through homomultimers or heteromultimers, and provided that enough receptors, FADD, or initiator caspases are expressed by a given cell line, selective inhibition of this pro-apoptotic signaling pathway can result from concomitant expression of any of the three antagonistic receptors, namely DcR1 (TRAIL-R3) [25,26], DcR2 (TRAIL-R4) [27,28], or a soluble receptor called OPG (osteoprotegerin) [29] (Figure 2). Amongst these antagonist receptors, OPG is probably the weakest inhibitor, owing to its lower affinity for TRAIL [30]. OPG exhibits much higher affinity for RANKL and its physiological function has, so far, mainly been ascribed to osteoclasts development and activation [31]. Nevertheless this soluble receptor was shown to be able to compete, to some extent, with DR4 or DR5 for TRAIL binding [29,32]. DcR1 and DcR2, on the other hand, owing to their higher affinity for TRAIL [26,30], have been studied more extensively to assess their ability to inhibit TRAIL pro-apoptotic signaling. These receptors are both devoid of functional DD and display differential inhibitory properties. While DcR1, whose c-terminus harbors a glycosylphosphatidyl-inositol (GPI) motif, is localized in lipid rafts, DR4, DR5, and DcR2 are mostly found in non-lipid rafts portions of the plasma membrane, even when engaged within the TRAIL DISC [33]. DcR1 is unable to form heteromultimers with DR4 or DR5 upon TRAIL stimulation. Therefore, like OPG, DcR1 appears to inhibit TRAIL-induced apoptosis in a competitive manner by titrating its cognate ligand [33]. DcR2, on the other hand, is co-recruited with DR4 [34] and DR5 [33] within the TRAIL DISC, in non-lipid rafts fractions (Figure 2). Recruitment of DcR2 within the TRAIL DISC leads to the formation of a heteromultimeric complex, whose ability to trigger initiator caspase activation is reduced, as compared to DR4 and/or DR5 homomultimeric or heteromultimeric complexes [33,34]. Since DcR2 is devoid of functional DD, it has been proposed that its recruitment within the TRAIL complex may impede caspase-8 activation by mere steric hindrance [35]. More recently, DcR1 and DcR2 were found to be able to act, in addition, in trans by titrating TRAIL on stroma cells within the tumor microenvironnement [36].


Marine Drugs Regulating Apoptosis Induced by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL).

Elmallah MI, Micheau O - Mar Drugs (2015)

Schematic representation of TRAIL pro-apoptotic proximal signaling regulation. Apoptosis induced by TRAIL is initiated through homo/or hetero-oligomerization of DR4 and/or DR5 and subsequent chain assembly of initiator caspases (1). Proximal activation of caspase-8 by these receptors can be inhibited by TRAIL antagonistic receptors DcR2 (2), DcR1, and OPG (3), as well as by the cellular caspase-8 inhibitor, c-FLIP (4) (see text for explanations).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663558&req=5

marinedrugs-13-06884-f002: Schematic representation of TRAIL pro-apoptotic proximal signaling regulation. Apoptosis induced by TRAIL is initiated through homo/or hetero-oligomerization of DR4 and/or DR5 and subsequent chain assembly of initiator caspases (1). Proximal activation of caspase-8 by these receptors can be inhibited by TRAIL antagonistic receptors DcR2 (2), DcR1, and OPG (3), as well as by the cellular caspase-8 inhibitor, c-FLIP (4) (see text for explanations).
Mentions: Efficient activation of initiator caspases, upon TRAIL stimulation, is tightly dependent on the quality of the DISC, determining the strength of activation of the initiator caspases [24]. Irrespective of whether the apoptotic signal is transduced by DR4 or DR5, through homomultimers or heteromultimers, and provided that enough receptors, FADD, or initiator caspases are expressed by a given cell line, selective inhibition of this pro-apoptotic signaling pathway can result from concomitant expression of any of the three antagonistic receptors, namely DcR1 (TRAIL-R3) [25,26], DcR2 (TRAIL-R4) [27,28], or a soluble receptor called OPG (osteoprotegerin) [29] (Figure 2). Amongst these antagonist receptors, OPG is probably the weakest inhibitor, owing to its lower affinity for TRAIL [30]. OPG exhibits much higher affinity for RANKL and its physiological function has, so far, mainly been ascribed to osteoclasts development and activation [31]. Nevertheless this soluble receptor was shown to be able to compete, to some extent, with DR4 or DR5 for TRAIL binding [29,32]. DcR1 and DcR2, on the other hand, owing to their higher affinity for TRAIL [26,30], have been studied more extensively to assess their ability to inhibit TRAIL pro-apoptotic signaling. These receptors are both devoid of functional DD and display differential inhibitory properties. While DcR1, whose c-terminus harbors a glycosylphosphatidyl-inositol (GPI) motif, is localized in lipid rafts, DR4, DR5, and DcR2 are mostly found in non-lipid rafts portions of the plasma membrane, even when engaged within the TRAIL DISC [33]. DcR1 is unable to form heteromultimers with DR4 or DR5 upon TRAIL stimulation. Therefore, like OPG, DcR1 appears to inhibit TRAIL-induced apoptosis in a competitive manner by titrating its cognate ligand [33]. DcR2, on the other hand, is co-recruited with DR4 [34] and DR5 [33] within the TRAIL DISC, in non-lipid rafts fractions (Figure 2). Recruitment of DcR2 within the TRAIL DISC leads to the formation of a heteromultimeric complex, whose ability to trigger initiator caspase activation is reduced, as compared to DR4 and/or DR5 homomultimeric or heteromultimeric complexes [33,34]. Since DcR2 is devoid of functional DD, it has been proposed that its recruitment within the TRAIL complex may impede caspase-8 activation by mere steric hindrance [35]. More recently, DcR1 and DcR2 were found to be able to act, in addition, in trans by titrating TRAIL on stroma cells within the tumor microenvironnement [36].

Bottom Line: Marine biomass diversity is a tremendous source of potential anticancer compounds.Its selectivity for cancer cells has attracted much attention in oncology.This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Faculty of Science, Helwan University, Ain Helwan, Cairo 11790, Egypt. mohamed_almallah@science.helwan.edu.eg.

ABSTRACT
Marine biomass diversity is a tremendous source of potential anticancer compounds. Several natural marine products have been described to restore tumor cell sensitivity to TNF-related apoptosis inducing ligand (TRAIL)-induced cell death. TRAIL is involved during tumor immune surveillance. Its selectivity for cancer cells has attracted much attention in oncology. This review aims at discussing the main mechanisms by which TRAIL signaling is regulated and presenting how marine bioactive compounds have been found, so far, to overcome TRAIL resistance in tumor cells.

Show MeSH
Related in: MedlinePlus