Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Wilson, Timothy R.; McEwan, Miranda; McLaughlin, Kylie A.; Clorennec, Christophe Le; Allen, Wendy L.; Fennell, Dean A.; Johnston, Patrick G.; Longley, Daniel B.

doi:10.1038/onc.2008.366

Cited by 48 publications

(49 citation statements)

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“…35 and 36). Many previous studies have shown that knockdown or downregulation of c-FLIP results in ligand-independent, but caspase-8-dependent, spontaneous apoptosis (37)(38)(39). Thus, our observation that ␥-secretase inhibitor, which inhibited the turnover of both c-FLIP L and c-FLIP S , also partially blocked PS1-induced apoptosis strongly suggests that PS1-induced apoptosis is at least partially mediated by ␥-secretase-catalyzed turnover of c-FLIP.…”

Section: Discussionsupporting

confidence: 57%

Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively

Zeng¹,

Zhang³

et al. 2015

Journal of Biological Chemistry

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Background: The PS1-induced apoptosis mechanism is not fully understood. Results: PS1-induced apoptosis depends on PSAP-Bax complex formation and ␥-catalyzed turnover of c-FLIP. Conclusion: PS1 induces apoptosis through the ␥-secretase-dependent PS1-c-FLIP-caspase-8-Bid cascade and ␥-secretaseindependent PS1-PSAP cascade, which converge on Bax to activate the mitochondrial apoptotic pathway. PS2 induced apoptosis through a different pathway. Significance: This study provides new insight into the mechanism of PS1-induced apoptosis.

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Section: Discussionsupporting

confidence: 57%

Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively

Zeng¹,

Zhang³

et al. 2015

Journal of Biological Chemistry

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“…For the other part, increasing caspase-8 activity, for example by downregulating c-FLIP, does not automatically convert type 2 into type 1 cells. 98 This can probably be attributed to the action of XIAP, 99 which can directly bind and inhibit the effector caspases (-3 and -7; and also active caspase-9, although with much weaker affinity). 79 High levels of XIAP would be predicted to attenuate Fas-induced apoptosis signalling at a much more downstream stage, targeting and blocking processed effector caspases.…”

Section: Xiap and Type 1 Versus Type 2 Fas-induced Apoptosis Signallingmentioning

confidence: 99%

Fas death receptor signalling: roles of Bid and XIAP

2011

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Fas (also called CD95 or APO-1), a member of a subgroup of the tumour necrosis factor receptor superfamily that contain an intracellular death domain, can initiate apoptosis signalling and has a critical role in the regulation of the immune system. Fas-induced apoptosis requires recruitment and activation of the initiator caspase, caspase-8 (in humans also caspase-10), within the death-inducing signalling complex. In so-called type 1 cells, proteolytic activation of effector caspases (-3 and -7) by caspase-8 suffices for efficient apoptosis induction. In so-called type 2 cells, however, killing requires amplification of the caspase cascade. This can be achieved through caspase-8-mediated proteolytic activation of the pro-apoptotic Bcl-2 homology domain (BH)3-only protein BH3-interacting domain death agonist (Bid), which then causes mitochondrial outer membrane permeabilisation. This in turn leads to mitochondrial release of apoptogenic proteins, such as cytochrome c and, pertinent for Fas death receptor (DR)-induced apoptosis, Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with low Pi), an antagonist of X-linked inhibitor of apoptosis (XIAP), which imposes a brake on effector caspases. In this review, written in honour of Juerg Tschopp who contributed so much to research on cell death and immunology, we discuss the functions of Bid and XIAP in the control of Fas DR-induced apoptosis signalling, and we speculate on how this knowledge could be exploited to develop novel regimes for treatment of cancer. (FasL) can induce apoptosis by a mechanism involving the adaptor protein FADD (Fas-associating protein with a novel death domain) and the proximal initiator caspase, caspase-8 (and in humans also caspase-10). Apoptosis can only be triggered by the membrane-bound form of FasL. Caspase-8 can activate the Bcl-2 homology (BH)3-only protein BH3-interacting domain death agonist (Bid), enabling a crosstalk to the intrinsic apoptotic pathway. Whereas FasL-stimulated type I cells can die independently of the intrinsic apoptotic machinery, type II cells depend on this crosstalk to mitochondria. X-linked inhibitor of apoptosis (XIAP) directly inhibits effector caspases and constitutes a discriminator between the type I and the type II Fas-induced apoptosis signalling. Besides apoptosis, Fas can trigger several non-apoptotic signalling pathways, including RIP1 kinase-dependent cell death (necroptosis), when caspase-8 is missing or disabled, as well as pathways that promote cell activation and cell proliferation. Open QuestionsHow is Fas-induced necroptosis and proliferation regulated at the molecular level? What is the role of XIAP's RING domain in Fas signalling? Why are certain Fas-expressing cell types refractory to FasL-induced killing? What are the roles of soluble FasL?The Death Receptor Fas Fas (also called CD95 or APO-1) is a member of the tumour necrosis factor receptor (TNF-R) superfamily, which also includes receptors for TNFa, TRAIL (TNF-related apoptosisinducing ligand), r...

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“…Experimental manipulation of FLIP (Wilson et al, 2007) and XIAP (Toscano et al, 2008;Connolly et al, 2009;Wilson et al, 2009) has confirmed their critical role in mediating resistance against TRAIL-R-dependent apoptosis. High levels of the anti-apoptotic proteins Bcl-xL (Schulze-Bergkamen et al, 2008), BAG-1 (Clemo et al, 2008), AKT, and Bax (Niyazi et al, 2009) also mediate TRAIL resistance in colorectal cell lines.…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

et al. 2010

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BACKGROUND: Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1). METHODS: This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecanbased regimens. All patients received two loading doses of mapatumumab (20 mg kg À1 every 14 days), followed by maintenance therapy with 10 mg kg À1 infused every 14 days. RESULTS: A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab. CONCLUSION: No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.

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Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Cited by 48 publications

References 49 publications

Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively

Cellular FLICE-like Inhibitory Protein (c-FLIP) and PS1-associated Protein (PSAP) Mediate Presenilin 1-induced γ-Secretase-dependent and -independent Apoptosis, Respectively

Fas death receptor signalling: roles of Bid and XIAP

Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer

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