Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks

Ivanisenko, Nikita V.; Seyrek, Kamil; Hillert-Richter, Laura K.; König, Corinna; Espe, Johannes; Bose, Kakoli; Lavrik, Inna N.

doi:10.1016/j.trecan.2021.12.002

Cited by 46 publications

(25 citation statements)

References 181 publications

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“…cFLIP is a regulator of the apoptotic signaling pathway and is expressed in various cancer cell lines ( 15 , 29 ). Previous studies have demonstrated that cFLIP expression levels are modulated at the proteasome-mediated post-translational level ( 30 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

“…The cellular Fas-associated death domain-like interleukin-1-converting enzyme-inhibitory protein (cFLIP) is an important apoptosis-regulatory protein associated with apoptosis (14). cFLIP has cFLIP L , cFLIP S and cFLIP R isoforms (15). Each of these isoforms has different effects on apoptotic pathways through different mechanisms (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Dapagliflozin induces apoptosis by downregulating cFILP_L and increasing cFILP_S instability in Caki‑1 cells

et al. 2022

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Dapagliflozin is a sodium/glucose cotransporter 2 inhibitor used recently to treat patients with type 2 diabetes. A recent study has demonstrated that dapagliflozin induces apoptosis in human renal and breast tumor cells. However, to the best of our knowledge, the molecular mechanism underlying dapagliflozin-mediated apoptosis in Caki-1 human renal carcinoma cells has not been elucidated. The present study demonstrated that the dapagliflozin treatment dose-dependently increased cell death in Caki-1 cells. Dapagliflozin treatment also induced apoptosis as confirmed by FITC-conjugated Annexin V/PI staining. Additionally, treatment with dapagliflozin reduced the expression levels of anti-apoptotic proteins, cellular Fas-associated death domain-like interleukin-1-converting enzyme-inhibitory protein (cFLIP) L and cFLIP S in Caki-1 cells. Benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone inhibited dapaglif lozin-induced apoptosis, implying that dapagliflozin-induced apoptosis is regulated by a caspase-dependent pathway. By contrast, N-acetylcysteine had no effect on dapagliflozin-induced apoptosis and downregulation of cFLIP L and cFLIP S expression. Furthermore, overexpression of cFLIP L , but not cFLIP S , partially inhibited apoptosis induced by dapagliflozin. cFLIP L and cFLIP S mRNA levels remained constant in Caki-1 cells after treatment with 0, 20, 40, 60, 80 and 100 µM dapagliflozin. Notably, it was confirmed that cFLIP S protein levels were reduced due to the increased cFLIP S instability in dapagliflozin-treated Caki-1 cells. The present study also demonstrated that dapagliflozin had no effect on HK-2 normal human kidney cells. Taken together, the present study revealed that dapagliflozin induced apoptosis via the downregulation of cFLIP L and an increase in cFLIP S instability, suggesting that dapagliflozin may be a feasible drug candidate for the treatment of human renal cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dapagliflozin induces apoptosis by downregulating cFILP_L and increasing cFILP_S instability in Caki‑1 cells

et al. 2022

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“…Recent studies have shown that c-FLIP prevents cells from undergoing apoptosis by impairing p53-mediated PUMA upregulation and caspase-8 activation [ 53 ]. However, the functions of c-FLIP are contradictory and depend on its abundance in the death-inducing signaling complex (DISC) [ 15 ], which is assembled from Fas, FADD, procaspase 8, and c-FLIP [ 54 ]. Low concentrations of c-FLIP in the DISC can cause the formation of a procaspase-8/c-FLIP heterodimer and promote caspase-8 activation [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cellular FLICE inhibitory protein, also known as c-FLIP, is a strong regulator of the extrinsic apoptosis pathway and competitively inhibits the binding of caspase-8 with FADD, thus avoiding the activation of caspase-8 [ 15 , 16 ]. c-FLIP expression is markedly decreased in thymocytes and hepatocytes in the absence of FAIM [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

FAIM Enhances the Efficacy of Mesenchymal Stem Cell Transplantation by Inhibiting JNK-Induced c-FLIP Ubiquitination and Degradation

Chen

Liu

et al. 2022

Stem Cells International

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Background. The poor survival rates of transplanted mesenchymal stem cells (MSCs) in harsh microenvironments impair the efficacy of MSCs transplantation in myocardial infarction (MI). Extrinsic apoptosis pathways play an important role in the apoptosis of transplanted MSCs, and Fas apoptosis inhibitory molecule (FAIM) is involved in regulation of the extrinsic apoptosis pathway. Thus, we aimed to explore whether FAIM augmentation protects MSCs against stress-induced apoptosis and thereby improves the therapeutic efficacy of MSCs. Methods. We ligated the left anterior descending coronary artery (LAD) in the mouse heart to generate an MI model and then injected FAIM-overexpressing MSCs (MSCsFAIM) into the peri-infarction area in vivo. Moreover, FAIM-overexpressing MSCs were challenged with oxygen, serum, and glucose deprivation (OGD) in vitro, which mimicked the harsh microenvironment that occurs in cardiac infarction. Results. FAIM was markedly downregulated under OGD conditions, and FAIM overexpression protected MSCs against OGD-induced apoptosis. MSCsFAIM transplantation improved cell retention, strengthened angiogenesis, and ameliorated heart function. The antiapoptotic effect of FAIM was mediated by cellular-FLICE inhibitory protein (c-FLIP), and FAIM augmentation improved the protein expression of c-FLIP by reducing ubiquitin–proteasome-dependent c-FLIP degradation. Furthermore, FAIM inhibited the activation of JNK, and treatment with the JNK inhibitor SP600125 abrogated the reduction in c-FLIP protein expression caused by FAIM silencing. Conclusions. Overall, these results indicated that FAIM curbed the JNK-mediated, ubiquitination–proteasome-dependent degradation of c-FLIP, thereby improving the survival of transplanted MSCs and enhancing their efficacy in MI. This study may provide a novel approach to strengthen the therapeutic effect of MSC-based therapy.

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“…c-Flip (cellular FADD-like interleukin 1β-converting enzyme (FLICE) inhibitory protein) acts as an anti-apoptotic protein by interfering with the activation of pro-caspase 8 in the receptor-mediated pathway [63]. Given its anti-apoptotic activity, it is not surprising that c-Flip is upregulated in many cancers and is used as a prognostic marker [64][65][66][67]. The transcriptional upregulation of c-Flip is controlled by a set of transcription factors including NFkB, CREB, and EGR1 [68][69][70].…”

Section: Discussionmentioning

confidence: 99%

Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells

Chang

Chen

Тихомиров

et al. 2022

Cancers

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Anthraquinone-based intercalating compounds, namely doxorubicin and mitoxantrone, have been used clinically based on their capacity to bind DNA and induce DNA damage. However, their applications have been limited by side effects and drug resistance. New-generation anthraquinone derivatives fused with different heterocycles have been chemically synthesized and screened for higher anticancer potency. Among the compounds reported in our previous study, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated 2c) was found to be apoptotic, but the direct cellular target responsible for the cytotoxicity remained unknown. Here, we report the synthesis and anticancer properties of two other derivatives, 4,11-bis(2-(2-chloroacetamidine)ethylamino)naphtho[2,3-f]indole-5,10-dione dihydrochloride (2a) and 4,11-bis(2-(2-chloroacetamidine)ethylamino)-2-methylanthra[2,3-b]furan-5,10-dione dihydrochloride (2b). We sought to identify and validate the protein target(s) of these derivatives in oral cancer cells, using molecular docking simulations and cellular thermal shift assays (CETSA). Our CETSA results illustrate that these derivatives targeted the tumor-associated NADH oxidase (tNOX, ENOX2), and their direct binding downregulated tNOX in p53-functional SAS and p53-mutated HSC-3 cells. Interestingly, the compounds targeted and downregulated tNOX to reduce SIRT1 deacetylase activity and increase Ku70 acetylation, which triggers c-Flip ubiquitination and induces apoptosis in oral cancer cells. Together, our data highlight the potential value of these heteroarene-fused anthraquinones in managing cancer by targeting tNOX and augmenting apoptosis.

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Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks

Cited by 46 publications

References 181 publications

Dapagliflozin induces apoptosis by downregulating cFILP_L and increasing cFILP_S instability in Caki‑1 cells

Dapagliflozin induces apoptosis by downregulating cFILP_L and increasing cFILP_S instability in Caki‑1 cells

FAIM Enhances the Efficacy of Mesenchymal Stem Cell Transplantation by Inhibiting JNK-Induced c-FLIP Ubiquitination and Degradation

Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells

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Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks

Cited by 46 publications

References 181 publications

Dapagliflozin induces apoptosis by downregulating cFILPL and increasing cFILPS instability in Caki‑1 cells

Dapagliflozin induces apoptosis by downregulating cFILPL and increasing cFILPS instability in Caki‑1 cells

FAIM Enhances the Efficacy of Mesenchymal Stem Cell Transplantation by Inhibiting JNK-Induced c-FLIP Ubiquitination and Degradation

Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells

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Dapagliflozin induces apoptosis by downregulating cFILP_L and increasing cFILP_S instability in Caki‑1 cells

Dapagliflozin induces apoptosis by downregulating cFILP_L and increasing cFILP_S instability in Caki‑1 cells