c-FLIP Mediates Resistance of Hodgkin/Reed-Sternberg Cells to Death Receptor–induced Apoptosis

Mathas, Stephan; Lietz, Andreas; Anagnostopoulos, Ioannis; Hummel, Franziska; Wiesner, Burkhard; Janz, Martin; Jundt, Franziska; Hirsch, Burkhard; Jöhrens-Leder, Korinna; Vornlocher, Hans‐Peter; Bommert, Kurt; Stein, Harald; Dörken, Bernd

doi:10.1084/jem.20031080

Cited by 185 publications

(184 citation statements)

References 64 publications

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“…34,35 Several studies have shown that functional blockade of antiapoptotic factors can either restore the apoptotic process in tumor cells or sensitize them to chemotherapy-and death ligand-induced apoptosis. 36,37 Accordingly, we showed that cancer cells express high levels of the antiapoptotic proteins PED/PEA-15, cFLIP, Bcl-xL and Bcl-2. This finding may explain why cancer cells despite expressing high levels of TRAIL-R1/R2 are refractory to apoptosis induction, even in the presence of high concentrations of a highly active recombinant form of TRAIL, and why at the same time they are resistant to the effects of conventional chemotherapeutic drugs.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

et al. 2008

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We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED, cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2. Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel treatment for epithelial cancers.

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Section: Discussionmentioning

confidence: 99%

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

et al. 2008

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“…In addition, we found that FLIP promotes resistance to chemotherapy, as FLIP gene silencing enhanced chemotherapy-induced cell death in vitro, and FLIP L overexpression conferred resistance to chemotherapeutic agents both in vitro and in vivo (Longley et al, 2006;Wilson et al, 2007). We and others have found that FLIP overexpression renders cells resistant to death ligands (Jonsson et al, 2003;Longley et al, 2006), whereas FLIP downregulation increases sensitivity (Yeh et al, 2000;Mathas et al, 2004;Galligan et al, 2005;Longley et al, 2006). Cell lines are classified as type I or II depending on whether they require mitochondrial involvement to induce apoptosis following death receptor activation.…”

Section: Discussionmentioning

confidence: 59%

“…The role of FLIP as a key regulator of death ligandinduced apoptosis is well established (Yeh et al, 2000;Mathas et al, 2004). We have demonstrated previously that silencing FLIP induces apoptosis in a panel of colorectal cancer cell lines in a manner that is dependent on caspase 8 and DR5, but that appears to be independent of DR5 ligation by TRAIL (Wilson et al, 2007).…”

Section: Discussionmentioning

confidence: 93%

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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“…In addition, the enhanced chemoresistance in the c-FLIP L -overexpressing lines may be due at least in part to c-FLIP L -activating intrinsic survival pathways such as those mediated by NF-kB and PI3 kinase Kataoka and Tschopp, 2004). Several studies have demonstrated that downregulating c-FLIP sensitizes various tumour cells to apoptosis induced by Fas agonists and TRAIL (Fulda et al, 2000;Poulaki et al, 2002;Mathas et al, 2004;Santiago et al, 2004). However, we are aware of only one other study that has demonstrated that downregulating c-FLIP sensitizes cancer cells to chemotherapy in the absence of cotreatment with a death receptor ligand.…”

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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c-FLIP Mediates Resistance of Hodgkin/Reed-Sternberg Cells to Death Receptor–induced Apoptosis

Cited by 185 publications

References 64 publications

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

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

c-FLIP inhibits chemotherapy-induced colorectal cancer cell death

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