Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Clarke, Penny; Tyler, Kenneth L.

doi:10.1007/s10495-006-0528-4

Cited by 28 publications

(26 citation statements)

References 64 publications

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“…Larochelle et al [1998] reported that Epstein-Barr virus-induced apoptosis may be mediated by FasL. Clarke and Tyler [2007] reported the reovirus-induced apoptosis via Tumor Necrosis Factor-related apoptosis-inducing ligand, and Kim et al [2007] reported that HIV could up-regulate the expression of Tumor Necrosis Factorrelated apoptosis-inducing ligand of antigen-presenting cell and induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

FasL/Fas pathway is involved in dengue virus induced apoptosis of the vascular endothelial cells

Liao¹,

Xu²,

Huang

2010

Journal of Medical Virology

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The hallmark of the dengue hemorrhagic fever/dengue shock syndrome is hematologic abnormality. The pathogenesis of dengue hemorrhagic fever/dengue shock syndrome remains unknown. Our work showed that the dengue virus serotype-2 induced apoptosis in human umbilical vein endothelial cells. Fas (CD95), Tumor Necrosis Factor receptors, and Tumor Necrosis Factor-related apoptosis-inducing ligand receptors are the most common death receptors, which can induce apoptosis. Compared with the untreated human umbilical vein endothelial cells, Fas expression was increased both in the mRNA level and on the surface of infected human umbilical vein endothelial cells. FasL was expressed at similar levels on human umbilical vein endothelial cells over a course of dengue virus serotype-2 infection, but the expression in mRNA level was increased in infected human umbilical vein endothelial cells. It is possible that there is soluble FasL secreted from human umbilical vein endothelial cells in the supernatant. Tumor Necrosis Factor-related apoptosis-inducing ligand receptor 1 and Tumor Necrosis Factor receptors 1-2 were constantly very low, whereas Tumor Necrosis Factor-related apoptosis-inducing ligand receptors 2-4 decreased after dengue virus serotype-2 infection. This result suggested that dengue virus serotype-2 may inhibit Tumor Necrosis Factor-related apoptosis-inducing ligand receptors-induced apoptosis. The apoptotic rates in human umbilical vein endothelial cells were decreased upon the addition of caspase family inhibitors. In addition, activated caspase 8 and caspase 3 were also observed by Western blot following dengue virus serotype-2 infection. Thus, it is shown that the Fas/FasL pathway may participate in dengue virus-induced apoptosis of vascular endothelial cells in vitro.

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Section: Discussionmentioning

confidence: 99%

FasL/Fas pathway is involved in dengue virus induced apoptosis of the vascular endothelial cells

Liao¹,

Xu²,

Huang

2010

Journal of Medical Virology

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“…Reoviruses are oncolytic viruses that multiply preferentially in tumor cells that harbor activated ras family or ras-signaling pathways, while sparing normal cells [127]. Recently, Clarke et al [128] demonstrated that reovirus infection results in the downregulation of c-FLIP and increased TRAIL-induced apoptosis in ovarian cancer cells, and overexpression of c-FLIP blocked reovirus-induced sensitization of these cells to TRAIL-induced apoptosis. Using oncolytic viruses aimed at downregulating c-FLIP may be potentially useful in combination with TRAIL and/or chemotherapeutic agents to eradicate cancer cells.…”

Section: Agents Known To Downregulate C-flipmentioning

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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“…Expression and modulation of expression has been examined in multiple tumour cell lines, including cell lines derived from carcinomas of the ovary, prostate, breast, urinary bladder and kidney [29][30][31][32][33][34]. In vivo, expression of these important caspase-8-inhibiting proteins has been shown in urothelial carcinomas, endometrial carcinomas and in Hodgkin lymphomas [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Caspase-8 and its inhibitors in RCCs in vivo: the prominent role of ARC

et al. 2008

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Activation of the initiator-caspase, caspase-8 is under tight control of multiple antiapoptotic regulators including ARC, cFlip(S), cFlip(L) and PED/PEA-15. Since there is little data regarding the expression of caspase-8 and its antiapoptotic regulators in human tumours in vivo, we analysed their expression in renal cell carcinomas (RCCs) to identify which of these genes might be crucial for the well known impaired apoptosis and--as a result--resistance towards chemotherapy and ionizing radiation of RCCs. Caspase-8, cFlip(S), cFlip(L) and PED/PEA-15 mRNA expression was significantly increased only in early stages of RCCs compared to non-neoplastic renal tissue. In contrast, ARC mRNA expression was significantly increased in RCCs of all stages without differences between the tumour stages and grades. Importantly, the relative mRNA expression ratio between ARC and caspase-8 was significantly increased during carcinogenesis and tumour progression. In contrast, the relative mRNA expression ratio between cFlip(S), cFlip(L) or PED/PEA-15 and caspase-8 remained constant during all tumour stages. In conclusion, our analysis revealed that ARC is the only caspase-8 inhibiting regulator being constantly overexpressed in RCCs. Furthermore, the balance between antiapoptotic ARC and proapoptotic caspase-8 is the only one to be disturbed during carcinogenesis and tumour progression of RCCs. This inhibition of Caspase-8 might therefore be one example for the multiple antiapoptotic functions of ARC in RCCs possibly contributing to the marked resistance of RCCs towards radio- and chemotherapy and reflects a shift of gene expression towards a more antiapoptotic context in RCCs.

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Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis

Cited by 28 publications

References 64 publications

FasL/Fas pathway is involved in dengue virus induced apoptosis of the vascular endothelial cells

FasL/Fas pathway is involved in dengue virus induced apoptosis of the vascular endothelial cells

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

Caspase-8 and its inhibitors in RCCs in vivo: the prominent role of ARC

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