Cellular FLICE-like Inhibitory Protein Long Form (c-FLIPL) Overexpression is Related to Cervical Cancer Progression

Ili, Carmen; Brebi-Mieville, Priscilla; Tapia, O.; Sandoval, Alejandra; López, Jaime; García, Patricia; Leal, Pamela; Sidransky, David; Guerrero-Preston, Rafael; Roa, Juan Carlos

doi:10.1097/pgp.0b013e31825d8064

Cited by 17 publications

(18 citation statements)

References 26 publications

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“…In one study of 462 colorectal cancer patients, FLIP(L) was identified as an independent marker of poor prognosis, whereas FLIP(S) (and TRAIL receptor) expression did not show a significant correlation with prognosis [121]. In a study of 536 cervical carcinoma samples, FLIP(L) expression increased in line with the grade of the carcinoma, although no significant relationship between FLIP and patient survival could be established [133]. In addition, in a study by our group, FLIP(L) mRNA was shown to significantly correlate with poorer overall survival of a cohort of AML patients [130].…”

Section: Flip Expression and Drug Resistance In Cancermentioning

confidence: 99%

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 Expression and Drug Resistance In Cancermentioning

confidence: 99%

FLIP as a therapeutic target in cancer

2018

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“…c-FLIP variants are also expressed in pancreatic intraepithelial neoplasms as well as pancreatic ductal adenocarcinomas, while c-FLIP was not detected in normal pancreatic ducts [77]. While the epithelium of the normal cervix and low-grade squamous intraepithelial lesions were mainly negative for c-FLIP, high-grade intraepithelial lesions as well as cancer samples showed increased c-FLIP expression [78]. This finding suggests that c-FLIP expression may serve as a potential cervical cancer progression marker.…”

Section: Upregulation Of C-flip In Human Cancersmentioning

confidence: 99%

Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy

2013

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Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5). This interaction in turn prevents Death-Inducing Signaling Complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.

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“…Alternatively increased expression of the anti-apoptotic protein c-FLIP can function upstream of caspase-8 to decrease apoptosis signaling [73]. Interestingly c-FLIP shows variable expression depending on tumor type and may represent a key mechanism of TRAIL-specific tumor escape [74,75,76]. Alternative mechanisms for resistance to TRAIL-mediated apoptosis includes the overexpression of the anti-apoptotic proteins Bcl-2 and Bcl-XL, both of which function to prevent mitochondrial release of cytochrome C and activation of the intrinsic apoptosis pathway [77,78].…”

Section: Modulation Of Tumor Necrosis Factor (Tnf)-related Apoptosmentioning

confidence: 99%

Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System

Sarhan

D’Arcy

Lundqvist

2014

IJMS

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The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients.

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Cellular FLICE-like Inhibitory Protein Long Form (c-FLIPL) Overexpression is Related to Cervical Cancer Progression

Cited by 17 publications

References 26 publications

FLIP as a therapeutic target in cancer

FLIP as a therapeutic target in cancer

Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy

Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System

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