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Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous mitochondria-dependent and exogenous death receptor pathways, and studies have shown that caspase-8-dependent external pathways appear to be more important than the activity of the intrinsic pathways. This paper reviews the regulation of anoikis by external pathways mediated by death receptors. Different death receptors bind to different ligands to activate downstream caspases. The possible mechanisms of Fas-associated death domain (FADD) recruitment by Fas and TNF receptor 1 associated-death domain (TRADD) recruitment by tumor necrosis factor receptor 1 (TNFR1), and DR4- and DR5-associated FADD to induce downstream caspase activation and regulate anoikis were reviewed. This review highlights the possible mechanism of the death receptor pathway mediation of anoikis and provides new insights and research directions for studying tumor metastasis mechanisms. 9w_3dtXFY6CUXRSJ-7gGif Video Abstract

When cells are exposed to death ligands such as TRAIL, a fraction undergoes apoptosis and a fraction survives; if surviving cells are re‐exposed to TRAIL, fractional killing is once again observed. Therapeutic antibodies directed against TRAIL receptors also cause fractional killing, even at saturating concentrations, limiting their effectiveness. Fractional killing arises from cell‐to‐cell fluctuations in protein levels (extrinsic noise), but how this results in a clean bifurcation between life and death remains unclear. In this paper, we identify a threshold in the rate and timing of initiator caspase activation that distinguishes cells that live from those that die; by mapping this threshold, we can predict fractional killing of cells exposed to natural and synthetic agonists alone or in combination with sensitizing drugs such as bortezomib. A phenomenological model of the threshold also quantifies the contributions of two resistance genes (c‐FLIP and Bcl‐2), providing new insight into the control of cell fate by opposing pro‐death and pro‐survival proteins and suggesting new criteria for evaluating the efficacy of therapeutic TRAIL receptor agonists. Synopsis Non‐genetic cell‐to‐cell variability results in fractional killing by TRAIL and therapeutic antibody agonists, limiting their effectiveness as anti‐cancer drugs. A simple model of initiator caspase dynamics reveals a threshold in caspase activity that separates dying and surviving cells. A model of initiator caspase activity is predictive of fractional killing by TRAIL. The model identifies a caspase activity threshold that is constant across dose and type of agonist. Therapeutic antibodies targeting TRAIL receptors kill poorly because this threshold is not crossed. The caspase activity threshold and classic MOMP threshold interact to determine cellular sensitivity to apoptosis inducers. Graphical Abstract Non‐genetic cell‐to‐cell variability results in fractional killing by TRAIL and therapeutic antibody agonists, limiting their effectiveness as anti‐cancer drugs. A simple model of initiator caspase dynamics reveals a threshold in caspase activity that separates dying and surviving cells.

PurposePancreatic cancer is a malignant tumor of the digestive system with poor prognosis and high mortality, and the treatment of pancreatic cancer still remains a major challenge. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis selectively in cancer cells while causing virtually no damage to normal cells, which is promising for cancer therapy. However, many primary tumors and cancer cell lines including various human pancreatic cancer cell lines were found to be resistant to TRAIL-induced apoptosis. Therefore, the purpose of the study was to improve antitumor effect of TRAIL on pancreatic cancer.MethodsThe 114–121 amino acid coding sequence “VRERGPQR” of wild type TRAIL protein that was selected changed into “RRRRRRRR”, and the novel membrane-penetrating peptide-alike mutant protein was named TRAIL-Mu3. The antitumor effect of TRAIL-Mu3 was analyzed both in vitro and in vivo. Western blotting, immunofluorescence and flow cytometry were used to investigate the underlying mechanisms.ResultsTRAIL-Mu3 could enhance the antitumor effects on pancreatic cancer cell lines, and the antitumor effect of TRAIL-Mu3 was stronger than gemcitabine in vivo. The immunofluorescence results suggested that TRAIL-Mu3 could remarkably enhance the affinity to pancreatic cancer cells. The Western blot results showed that treatment with TRAIL-Mu3 caused a clear cleavage of caspase-3 and caspase-8. In addition, both the Western blot and flow cytometry suggested a significantly up-expression of DR5 in TRAIL-Mu3 group.ConclusionsMembrane-penetrating peptide-alike mutant-TRAIL-Mu3 induced pancreatic cancer cell death more efficiently than TRAIL, and this effect was supposed to be mediated by the increased affinity to cell membrane, the up-regulation of DR5 and the enhancement of activated caspase.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and agonistic anti-DR4/TRAIL-R1 and anti-DR5/TRAIL-R2 antibodies are currently under clinical investigation for treatment of different malignancies. TRAIL activates DR4 and DR5 and thereby triggers apoptotic and non-apoptotic signaling pathways, but possible different roles of DR4 or DR5 in these responses has poorly been addressed so far. In the present work, we analyzed cell viability, DISC formation as well as IL-8 and NF–κB activation side by side in responses to TRAIL and agonistic antibodies against DR4 (mapatumumab) and against DR5 (lexatumumab) in pancreatic ductal adenocarcinoma cells. We found that all three reagents are able to activate cell death and pro-inflammatory signaling. Death-inducing signaling complex (DISC) analysis revealed that mapatumumab and lexatumumab induce formation of homocomplexes of either DR4 or DR5, whereas TRAIL additionally stimulated the formation of heterocomplexes of both receptors. Notably, blocking of receptors using DR4- and DR5-specific Fab fragments indicated that TRAIL exerted its function predominantly via DR4. Interestingly, inhibition of PKC by Goe6983 enabled DR5 to trigger apoptotic signaling in response to TRAIL and also strongly enhanced lexatumumab-mediated cell death. Our results suggest the existence of mechanisms that silence DR5 for TRAIL- but not for agonistic-antibody treatment.

Our study aimed to compare death signalling pathways triggered by lupulone in TRAIL-sensitive human colon cancer cells (SW480) and in their derived TRAIL-resistant metastatic cells (SW620). Lupulone (40 μg/ml) up-regulated expression of TRAIL DR4/DR5 death receptors at the cell surface of both cell lines, even in the absence of exogenous TRAIL ligand. Cell death induced by lupulone was inhibited in SW480 and SW620 cells exposed to blocking anti-DR4/DR5 antibodies. In SW480 cells, lupulone triggered cell death through a cross-talk between TRAIL-DR4/DR5 and the mitochondrial (intrinsic) pathways involving caspase-8 activation and Bid protein cleavage. As a consequence mitochondrial cytochrome c was released into the cytosol and activation of caspases-9 and -3 was observed. In the metastatic SW620 cells, lupulone restored the sensibility of these cells to TRAIL ligand and activated the extrinsic apoptotic pathway via DR4/DR5 death receptors and the involvement of the caspase-8/caspase-3 cascade. The demonstration that lupulone is able to activate TRAIL-death signalling pathways even in TRAIL resistant cancer cells highlights the potential of this natural compound for cancer prevention and therapy.