c‐Flip protein expression in Burkitt's lymphomas is associated with a poor clinical outcome

Valnet-Rabier, Marie-Blanche; Challier, Bruno; Thiébault, Sylvie; Angonin, R.; Margueritte, Geneviève; Mougin, Christiane; Kantélip, B.; Deconinck, Eric; Cahn, Jean‐Yves; Fest, Thierry

doi:10.1111/j.1365-2141.2005.05378.x

Cited by 65 publications

(55 citation statements)

References 37 publications

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“…FLIP has been found to be overexpressed in many human cancers (Ryu et al, 2001;Zhou et al, 2004;Valnet-Rabier et al, 2005), and has emerged through our work and that of others, as a potential anti-cancer drug target (Hyer et al, 2005;Wilson et al, 2007). Furthermore, XIAP has been found to be overexpressed in several cancers, and small molecule and antisense approaches to target XIAP are in development (Hu et al, 2003;LaCasse et al, 2006).…”

Section: Discussionmentioning

confidence: 72%

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

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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Section: Discussionmentioning

confidence: 72%

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

et al. 2008

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“…Moreover, c-FLIP overexpression accelerated progression to androgen independence by inhibiting apoptosis in LNCaP prostate tumors implanted in nude mice [77]. Similarly, c-FLIP is also an independent prognostic indicator in colorectal carcinomas [56], and its expression in Burkitt's lymphomas is also associated with a poor clinical outcome and could be a reliable prognostic factor in this type of cancer [78]. Furthermore, recent studies show that c-FLIP expression may contribute to the carcinogenesis and aggressiveness of endometrial carcinomas and may serve as a useful prognostic factor for this tumor [79,80].…”

Section: C-flip Functionmentioning

confidence: 99%

Cellular FLICE-Like Inhibitory Protein (C-FLIP): A Novel Target for Cancer Therapy

Safa

Day

2008

CCDT

162

187

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Cellular FLICE-like inhibitory protein (c-FLIP) has been identified as a protease-dead, procaspase-8-like regulator of death ligand-induced apoptosis, based on observations that c-FLIP impedes tumor necrosis factor-α (TNF-α), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by binding to FADD and/or caspase-8 or -10 in a ligand-dependent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIP is a family of al ternatively spliced variants, and primarily exists as long (c-FLIP L ) and short (c-FLIP S ) splice variants in human cells. Although c-FLIP has apoptogenic activity in some cell contexts, which is currently attributed to heterodimerization with caspase-8 at the DISC, accumulat ing evidence indicates an anti-apoptotic role for c-FLIP in various types of human cancers. For example, small interfering RNAs (siRNAs) that specifically knocked down expression of c-FLIP L in diverse human cancer cell lines, e.g., lung and cervical cancer cells, augmented TRAIL-induced DISC recruitment, and thereby enhanced effector caspase stimulation and apoptosis. Therefore, the outlook for the therapeutic index of c-FLIP-targeted drugs appears excellent, not only from the efficacy observed in experimental models of cancer therapy, but also because the current understanding of dual c-FLIP action in normal tissues supports the notion that c-FLIP-targeted cancer therapy will be well tolerated. Interestingly, Taxol, TRAIL, as well as several classes of small molecules induce c-FLIP downregulation in neoplastic cells. Efforts are underway to develop small-molecule drugs that induce c-FLIP downregulation and other c-FLIP-targeted cancer therapies. In this review, we assess the outlook for improving cancer therapy through c-FLIP-targeted therapeutics.

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“…poor prognosis in Burkitt's lymphoma. 71 In HTLV-1 + Tacute lymphoblastic leukemia (T-ALL) Tax protein induces strong expression of c-FLIP in leukemic blasts, responsible for their resistance to TRAIL and FasL-mediated apoptosis.…”

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confidence: 99%

Deregulation of apoptosis in acute myeloid leukemia

Testa¹,

Riccioni²

2007

Haematologica

131

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Apoptosis, or programmed cell death, is central to the development and homeostasis of the hematopoietic system. Dysregulation of apoptosis plays an important role in the development of a variety of human pathologies, including cancer, autoimmune diseases and neurodegenerative disorders. Studies carried out in the last years have shown that leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells over their normal counterpart. Furthermore, abnormalities in the apoptotic response also play a role in the development of drug resistance by leukemic cells. The identification of the different components of the apoptotic pathways has enabled the detection of various biochemical defects present in leukemic cells compared to their normal counterparts. These defects contribute to the survival advantage of the leukemic clone over the normal hematopoietic cells and are also frequently associated with a low rate of response to standard chemotherapy treatment and with poor survival. Furthermore, these findings have lead to the identification of many potential apoptotic targets for the development of new drugs targeting anti-apoptotic molecules abnormally expressed or regulated in leukemic cells. Many of these drugs restore the sensitivity of leukemic cells to apoptotic stimuli and some of them are under investigation at a clinical level.

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c‐Flip protein expression in Burkitt's lymphomas is associated with a poor clinical outcome

Cited by 65 publications

References 37 publications

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

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

Cellular FLICE-Like Inhibitory Protein (C-FLIP): A Novel Target for Cancer Therapy

Deregulation of apoptosis in acute myeloid leukemia

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