SAHA overcomes FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma

Crawford, Nyree; Stasik, Izabela; Holohan, Caitriona; Majkut, Joanna; McGrath, Mike; Johnston, Patrick G.; Chessari, Gianni; Ward, George A.; Waugh, David J.; Fennell, Dean A.; Longley, Daniel B.

doi:10.1038/cddis.2013.258

Cited by 28 publications

(31 citation statements)

References 39 publications

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“…Not surprisingly, there is a wealth of data showing that FLIP is key determinant of resistance to TRAIL receptor agonists; however, it remains to be seen whether high FLIP expression will be a key clinical mechanism of resistance to the next generation of multi-valent TRAIL receptor agonists. We have also reported that FLIP is an important determinant of resistance to IAP antagonists, with FLIP preventing cell death induced in response to both monovalent and bivalent IAP antagonists by blocking caspase-8 activation at the ripoptosome [146,147]. More recently, we reported that acute induction of FLIP expression in response to MEK inhibition in BRAF mutant colorectal cancer results in resistance to MEK inhibitor-induced cell death [148].…”

Section: Flip As a Mediator Of Therapy Resistancementioning

confidence: 88%

FLIP as a therapeutic target in cancer

2018

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One of the classic hallmarks of cancer is disruption of cell death signalling. Inhibition of cell death promotes tumour growth and metastasis, causes resistance to chemo‐ and radiotherapies as well as targeted agents, and is frequently due to overexpression of antiapoptotic proteins rather than loss of pro‐apoptotic effectors. FLIP is a major apoptosis‐regulatory protein frequently overexpressed in solid and haematological cancers, in which its high expression is often correlated with poor prognosis. FLIP, which is expressed as long (FLIP(L)) and short (FLIP(S)) splice forms, achieves its cell death regulatory functions by binding to FADD, a critical adaptor protein which links FLIP to the apical caspase in the extrinsic apoptotic pathway, caspase‐8, in a number of cell death regulating complexes, such as the death‐inducing signalling complexes (DISCs) formed by death receptors. FLIP also plays a key role (together with caspase‐8) in regulating another form of cell death termed programmed necrosis or ‘necroptosis’, as well as in other key cellular processes that impact cell survival, including autophagy. In addition, FLIP impacts activation of the intrinsic mitochondrial‐mediated apoptotic pathway by regulating caspase‐8‐mediated activation of the pro‐apoptotic Bcl‐2 family member Bid. It has been demonstrated that FLIP can not only inhibit death receptor‐mediated apoptosis, but also cell death induced by a range of clinically relevant chemotherapeutic and targeted agents as well as ionizing radiation. More recently, key roles for FLIP in promoting the survival of immunosuppressive tumour‐promoting immune cells have been discovered. Thus, FLIP is of significant interest as an anticancer therapeutic target. In this article, we review FLIP's biology and potential ways of targeting this important tumour and immune cell death regulator.

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Section: Flip As a Mediator Of Therapy Resistancementioning

confidence: 88%

FLIP as a therapeutic target in cancer

2018

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“…FLIP is a major apoptosis-regulatory protein frequently overexpressed in solid and hematological cancers and is an important mediator of chemo-and radio-resistance as well as apoptosis induced by immune effector cells and therapeutic agonists [35][36][37][38] . For these reasons, high FLIP expression has been correlated with poor prognosis in a number of cancers.…”

Section: Discussionmentioning

confidence: 99%

Regulation of FLIP(L) and TRAIL-R2 signalling by the SCF^Skp2Ubiquitin Ligase Complex

Longley

Roberts

Holohan

et al. 2019

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Depending on its expression levels, the long splice form of the pseudo-caspase FLIP (FLIP(L)) can act as an inhibitor (high expression) or activator (low expression) of apoptosis induction by the TRAIL-R2 death-inducing signalling complex (DISC); its expression levels are therefore tightly regulated. Here, we demonstrate that the Skp1-Cullin-1-F-box (SCF) Cullin-Ring E3 Ubiquitin Ligase complex containing Skp2 (SCF Skp2 ) regulates the stability of FLIP(L) (but not the short splice form FLIP(S)), and, unusually, this is mediated by direct binding of FLIP(L) to Cullin-1 rather than via Skp2. By fine mapping the interaction of FLIP(L) with Cullin-1 to the large subunit of its pseudo-caspase domain, we found that the interaction is significantly stronger with FLIP(L)'s DISC-processed p43-form.Importantly, this interaction disrupts the ability of p43-FLIP to interact with FADD, caspase-8 and another DISC component, TRAF2. Moreover, we find that SCF Skp2 associates with TRAIL-R2 constitutively and does so independently of FLIP(L) and other canonical DISC components. Inhibition of Cullin-1 expression (using siRNA) or activity (using a NEDDylation inhibitor, MLN4924) enhanced FLIP(L) and TRAF2 levels at the TRAIL-R2 DISC and enhanced caspase-8 processing. This suggests that processing of FLIP(L) to p43-FLIP at the TRAIL-R2 DISC enhances its interaction with co-localised SCF Skp2 , leading to disruption of p43-FLIP's association with the DISC thereby altering caspase-8 processing. These findings provide important new insights into how FLIP(L) expression and TRAIL-R2 signaling is controlled. Regulation of FLIP(L) and TRAIL signalling by SCF Skp2JZ Roberts et al. 3 IntroductionProgrammed cell death (apoptosis) plays a key role in maintaining normal tissue homeostasis and preventing disease 1 . Apoptosis is orchestrated by a family of cysteine proteases, the caspases 2 . The multi-protein complexes formed following activation of the CD95 (Fas) and TRAIL-R1/R2 (DR4/DR5) death receptors by their ligands (FasL and TRAIL) expressed by immune effector cells and by 2 nd generation therapeutic agonists (ABBV621 and MEDI3039) is called the death-inducing signalling complex (DISC), consisting of the receptors, the adaptor molecule FADD, procaspase-8 and FLIP 3 .Recruitment into these complexes exposes FADD's N-terminal death effector domain (DED), which recruits procaspase-8 by interacting with its N-terminal tandem DEDs 4 . Procaspase-8 homodimerization results in conformational changes in its catalytic domains that lead to its activation 5 . Two main splice forms of FLIP have been identified in humans: a long form (FLIP(L)) and a short form (FLIP(S)), both of which contain tandem DEDs and can be recruited to the DISC and related complexes (such as TNFR1 Complex II and the ripoptosome) where they form heterodimers with procaspase-8 4 . The relative amounts of FLIP(S) and FLIP(L) recruited to these complexes is a key determinant of cell fate (survival, apoptosis or necroptosis) and whether FLIP(L) acts as an inhibitor or activator o...

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“…MPM show aberrant CpG island methylation compared to normal pleura [39,40], even with an age [41]-and ethnicity [42,43] e dependent manner and it is the promoter of several known tumorsupressor genes that is methylated in MPM [44]. This Are small non-coding RNA molecules that regulate gene expression by binding to mRNA targets leading to their degradation or inhibiting their translation mTOR pathway mTOR (mammalian target of rapamycin) is a key protein which when activated leads to increased production of multiple proteins' [45,46]. The Wnt signaling pathway is deregulated by promoter methylation of its regulatory genes in MPM.…”

Section: In Favor Of Mpmmentioning

confidence: 99%