Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma

Zhou, Xiaodong; Yu, Jie-Ping; Liu, Jin; Luo, Haitao; Chen, Hongxia; Yu, Honggang

doi:10.1042/cs20030238

Cited by 63 publications

(69 citation statements)

References 38 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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“…In both studies, increased c-FLIP S protein expression correlated with decreased caspase-8 processing at the Fas-mediated death-inducing signaling complex (44,45). Other studies indicate a role for elevated c-FLIP S in the survival of various tumor cells, including human gastric cancers (55,56) and cells from patients with myelodysplastic syndrome (57). We propose an alternative mechanism of generating p27FLIP by further cleavage of p43FLIP.…”

Section: Discussionmentioning

confidence: 88%

Effector CD4+ T Cells Generate Intermediate Caspase Activity and Cleavage of Caspase-8 Substrates

Misra

Jelley-Gibbs

Russell

et al. 2005

The Journal of Immunology

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Caspase-8 activation promotes cell apoptosis but is also essential for T cell activation. The extent of caspase activation and substrate cleavage in these divergent processes remains unclear. We show that murine effector CD4+ T cells generated levels of caspase activity intermediate between unstimulated T cells and apoptotic populations. Both caspase-8 and caspase-3 were partially activated in effector T cells, which was reflected in cleavage of the caspase-8 substrates, c-FLIPL, receptor interacting protein 1, and to a lesser extent Bid, but not the caspase-3 substrate inhibitor of caspase-activated DNase. Th2 effector CD4+ T cells manifested more caspase activity than did Th1 effectors, and caspase blockade greatly decreased initiation of cell cycling. The current findings define the level of caspase activity and substrates during initiation of T cell cycling.

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“…Furthermore, clinical studies have demonstrated significantly elevated c-FLIP expression in colorectal and gastric tumours (Ryu et al, 2001;Zhou et al, 2004), suggesting that c-FLIP may be a relevant clinical target not only in CRC but also in gastric cancer, where 5-FU-based chemotherapy regimens are also used. Moreover, our data suggest that c-FT therapeutic strategies may be effective against colorectal tumours irrespective of p53 mutational status.…”

Section: Discussionmentioning

confidence: 99%

c-FLIP inhibits chemotherapy-induced colorectal cancer cell death

et al. 2005

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c-FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5. We studied the effect of c-FLIP on the apoptotic response to chemotherapies used in colorectal cancer (CRC) (5-fluorouracil, oxaliplatin and irinotecan). Simultaneous downregulation of both c-FLIP splice forms c-FLIP L and c-FLIP S with siRNA synergistically enhanced chemotherapy-induced apoptosis in p53 wild-type (HCT116p53 þ / þ , RKO), null (HCT116p53 À/À ) and mutant (H630) CRC cell lines. Furthermore, overexpression of c-FLIP L , but not c-FLIP S , potently inhibited apoptosis induced by chemotherapy in HCT116p53 þ / þ cells, suggesting that c-FLIP L was the more important splice form in mediating chemoresistance. In support of this, siRNA specifically targeted against c-FLIP L synergistically enhanced chemotherapy-induced apoptosis in a manner similar to the siRNA targeted against both splice forms. Inhibition of caspase 8 blocked the enhanced apoptosis induced by c-FLIP-targeted (FT) siRNA and chemotherapy. Furthermore, we found that downregulating cell surface DR5, but not Fas, also inhibited apoptosis induced by FT siRNA and chemotherapy. Interestingly, these effects were not dependent on activation of DR5 by its ligand TRAIL. These results indicate that c-FLIP inhibits TRAILindependent, DR5-and caspase 8-dependent apoptosis in response to chemotherapy in CRC cells. Moreover, targeting c-FLIP in combination with existing chemotherapies may have therapeutic potential for the treatment of CRC.

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Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma

Cited by 63 publications

References 38 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

Effector CD4+ T Cells Generate Intermediate Caspase Activity and Cleavage of Caspase-8 Substrates

c-FLIP inhibits chemotherapy-induced colorectal cancer cell death

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