Overexpression of cFLIP in head and neck squamous cell carcinoma and its clinicopathologic correlations

Li, Xiuguo; Pan, Xinliang; Zhang, Hui; Lei, Dapeng; Liu, Dayu; Xu, Fenglei; Luan, Xiying

doi:10.1007/s00432-007-0325-7

Cited by 22 publications

(17 citation statements)

References 26 publications

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“…Furthermore, the overexpression of cFLIP attenuated apoptosis induced by FPDHP. cFLIP has been identified as an inhibitor of apoptosis triggered by the engagement of death receptors, such as Fas or TRAIL, and abnormal cFLIP expression has been identified in various types of cancer (21,22). Therefore, this suggests that the transcriptional downregulation of cFLIP by FPDHP may be important for the induction of FPDHP-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 96%

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Park

Kim

et al. 2014

International Journal of Molecular Medicine

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Abstract. The inhibition of topoisomerase can suppress the growth of cancer cells and induce apoptosis. The aim of this study was to evaluate the anticancer effects and mechanisms of action of a novel topoisomerase inhibitor, 4-(furan-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-1,10-phenanthroline (FPDHP). FPDHP suppressed the growth of Caki, A549, HT29 and MDA-MB-231 cells, and induced caspase-dependent apoptosis in the Caki cells. In particular, FPDHP also induced caspase-dependent apoptosis and the downregulation of the protein expression levels of cellular FLICE-like inhibitory protein (cFLIP) and the phosphorylation of Akt in Caki cells. Notably, the overexpression of cFLIP, but not that of Akt, in part, blocked the FPDHP-mediated apoptosis in Caki cells. In addition, FPDHP was further shown to induce the caspase-independent detachment of Caki cells from the culture dish; higher populations of apoptotic cells were observed in the detached cells than in the attached cells. To the best of our knoweledge, these results collectively demonstrate for the first time that FPDHP has a killing effect on Caki cells, which is mediated through both caspase-dependent apoptosis and caspase-independent cell detachment.

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Section: Discussionmentioning

confidence: 96%

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

Park

Kim

et al. 2014

International Journal of Molecular Medicine

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“…The results showed that these genes were downregulated when IKKa and IKKb were knocked down in both in vivo and in vitro assays. The c-FLIP and Bcl-xl were highly expressed in human malignancy, [28][29][30][31][32] and we found that the transcription level of c-FLIP was significantly increased in human HCC tissue, whereas there was no difference in Bcl-xl transcription level. Nevertheless, Bcl-xl is a significant prognostic factor for disease progression in human HCC, because the actual effect of this gene is not determined by its expression level but rather by the rate of deamidation.…”

Section: Discussionmentioning

confidence: 99%

High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer

Jiang

Xia

et al. 2009

Intl Journal of Cancer

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IKK-NF-jB signaling is regarded as an important factor in hepatocarcinogenesis and a potential target for liver cancer therapy. Therefore, in this study, we analyzed the expression of mRNAs encoding components and targets of NF-jB signaling including IKKa, IKKb, RANK, RANKL, OPG, CyclinD3, mammary serine protease inhibitor (Maspin), CyclinD1, c-FLIP, Bcl-xl, Stat3, Cip1 and Cip2 by real-time PCR in 40 patients with liver cancer. After statistical analysis, 7 indices including IKKa, IKKb, RANK, Maspin, c-FLIP, Cip2 and cyclinD1 were found to show significant differences between tumor tissue and its corresponding adjacent tissue. When IKKa and IKKb were downregulated in the hepatocellular carcinoma (HCC) cell lines of MHCC-97L and MHCC-97H in vitro, the numbers of BrdU positive cells were decreased in both IKKa and IKKb knockdown cells. Levels of apoptosis were also investigated in IKKa and IKKb knockdown cells. The growth of HCC was inhibited in the subcutaneous implantation model, and lung metastatogenesis was also significantly inhibited in the kidney capsule transplantation model. Downregulation of IKKa and IKKb in HCC cultured in vitro revealed that increased Maspin, OPG and RANKL expression was associated with metastasis of HCC. These findings were associated with downregulation of Bcl-XL and c-FLIP, which may be the reason for increased apoptosis. The therapeutic effect of IKKa and IKKb downregulation depends on extent of NF-jB inhibition and the malignant nature of the HCC. We anticipate that IKK-targeted gene therapy can be used in the treatment of HCC, a cancer that is notoriously resistant to radiation and chemotherapy.

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“…Elevated expression levels of c-FLIP have been reported in colorectal cancer [67,68], bladder urothelial cancer [69], cervical cancer [70], Burkitt's lymphoma [71], non-Hodgkin's lymphoma [72], Head and Neck Squamous Cell Carcinoma (HNSCC) [73], hepatocellular cancers [74], and high-grade prostatic intraepithelial neoplasia (HGPIN) with maximal c-FLIP expression detected in Castrate-Resistant Prostate Cancer (CRPC) [75]. c-FLIP upregulation is also seen in gastric cancer and plays an important role in lymph node metastasis, which ultimately contributes to tumor progression [76].…”

Section: Upregulation Of C-flip In Human Cancersmentioning

confidence: 99%

Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy

2013

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Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5). This interaction in turn prevents Death-Inducing Signaling Complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.

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Overexpression of cFLIP in head and neck squamous cell carcinoma and its clinicopathologic correlations

Abstract: Overexpression of cFLIP(L) is a frequent event in HNSCC and HNSCC cells in vivo may need it to evade apoptosis mediated by Fas or other receptors, which might contribute to tumour development and progression.

Cited by 22 publications

References 26 publications

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

FPDHP, a novel anticancer agent, induces cell detachment and caspase-dependent apoptosis in Caki cells

High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer

Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy

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