Targeting c-FLIP in cancer

Shirley, Sarah; Micheau, Olivier

doi:10.1016/j.canlet.2010.10.009

Cited by 128 publications

(145 citation statements)

References 117 publications

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“…2B and C). The mechanisms of the downregulation of FLIP have been reported by several studies, showing the induction of proteasomal degradation and the inhibition of transcriptional regulation (28). In this study, the expression of FLIP mRNA was drastically suppressed by the combined treatment (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 62%

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

Toriyama

Horinaka

Yasuda

et al. 2016

Molecular Cancer Therapeutics

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The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of death receptor 5 (DR5). We identified that knockdown of DR5 by small interfering RNA (siRNA) significantly suppressed apoptosis by the combined treatment. Therefore, we conjectured that the apoptosis induced by OBP-801 and celecoxib is at least partially dependent on DR5. However, it was interesting that the combined treatment drastically suppressed expression of DR5 ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). These data suggest that there is no involvement of TRAIL in the induction of apoptosis by the combination, regardless of the dependence of DR5. Moreover, xenograft studies using human bladder cancer cells showed that the combined therapy suppressed tumor growth by upregulating expressions of DR5 and Bim. The inhibition of tumor growth was significantly more potent than that of each agent alone, without significant weight loss. This combination therapy provided a greater benefit than monotherapy in vitro and in vivo. These data show that the combination therapy with OBP-801 and celecoxib is a potential novel therapeutic strategy for patients with muscle-invasive bladder cancer. Mol Cancer Ther; 15(9); 2066-75. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 62%

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

Toriyama

Horinaka

Yasuda

et al. 2016

Molecular Cancer Therapeutics

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“…c-FLIP is a target in cancer therapy. Small-molecule drugs and c-FLIP-specific siRNA that downregulates c-FLIP have been developed (45,46). Additionally, many chemotherapeutics exhibit the ability to inhibit c-FLIP expression.…”

Section: Discussionmentioning

confidence: 99%

Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

et al. 2015

The Journal of Immunology

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Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor–induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b+ conventional DCs (cDCs), CD8+ cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow–derived DCs (BMDCs) displayed enhanced production of TNF-α, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP–deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP+/− macrophages. Additionally, the increased activation in c-FLIP–deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity.

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“…Some reports have also demonstrated that down-regulation of c-FLIP in vitro can restore apoptosis mediated by TRAIL and CD95L. Thus, c-FLIP can be utilized as a promising target for cancer therapy, particularly if combined with other treatments, for example, TRAIL or conventional chemotherapy (Sung et al, 2010;Shirley and Micheau, 2013). In contrast to the anti-apoptotic role of c-FLIP at high levels of expression, c-FLIPL has been demonstrated to induce apoptosis at low and more physiologically relevant expression levels by recruiting at the DISC to increase caspase-8 activation (Chang et al, 2002).…”

Section: Role Of Apoptosis In Cancermentioning

confidence: 99%

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Goldar¹,

Khaniani²,

Derakhshan³

et al. 2015

Asian Pacific Journal of Cancer Prevention

486

338

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Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c-FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis.

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Targeting c-FLIP in cancer

Cited by 128 publications

References 117 publications

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

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