Cisplatin unleashes Toll-like receptor 3-mediated apoptosis through the downregulation of c-FLIP in malignant mesothelioma

Vanbervliet-Defrance, Béatrice; Delaunay, Tiphaine; Daunizeau, Thomas; Képénékian, Vahan; Gléhen, Olivier; Weber, Kathrin; Estornes, Yann; Ziverec, Audrey; Djemal, Leïla; Delphin, Marion; Lantuéjoul, Sylvie; Passot, Guillaume; Grégoire, Marc; Micheau, Olivier; Blanquart, Christophe; Renno, Toufic; Fonteneau, Jean-François; Lebecque, Serge; Mahtouk, Karène

doi:10.1016/j.canlet.2019.12.016

Cited by 16 publications

(12 citation statements)

References 41 publications

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“…However, one of limitations in this study points to the fact that Poly(I:C), a synthetic analog of dsRNA can activate the signaling via both TLR3 and cytoplasmic dsRNA sensors such as melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). Although most studies have been demonstrated that Poly(I:C) induced apoptosis in a TLR3-dependent manner [ 34 , 36 , 61 ], our current study needs further characterization to support the specific role of TLR3-mediated apoptosis and necroptosis in CCA cells.…”

Section: Discussionmentioning

confidence: 81%

“…S 2 A, B). We therefore tentatively hypothesized that the responsiveness to Poly(I:C) stimulation could be possibly influenced by negative regulators including cellular inhibitor of apoptosis proteins (cIAP1 and cIAP2) [ 37 , 60 ] and cellular FLICE-like inhibitory protein (c-FLIP) [ 33 , 36 ] (Fig. S 3 A, B).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, in vivo anti-tumor effects of TLR3 ligand, Poly(I:C) are possibly mainly due to an induction of cell death upon direct stimulation of TLR3 by TLR3 ligand, Poly(I:C) [24] and also the recruitment of tumor-specific CD8+ T lymphocytes [71]. TLR3 ligand, Poly(I:C) stimulation has been reported to induce cell death on itself or combination with sensitizers in several cancers, but lack of evidence in CCA [18][19][20][21][22][23][24][25][26][27][28][29][30][31][33][34][35][36]. Our results did demonstrate for the first time that Poly(I:C) itself did not induce CCA cell death but only in the presence of Smac mimetic, an IAP antagonist [72], the combination treatment significantly triggered apoptosis with high synergism.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, TLR3 ligands have been studied in clinical trials as adjuvants for cancer immunotherapy to enhance cancer vaccine efficacy [ 15 – 17 ]. In addition to orchestrating inflammatory and immune responses, triggering TLR3 signaling by TLR3 ligands has been reported to directly kill various cancer cells such as breast cancer [ 18 , 19 ], melanoma [ 20 , 21 ], renal cell carcinoma (RCC) [ 22 ], prostate cancer [ 23 , 24 ], nasopharyngeal carcinoma [ 25 , 26 ], multiple myeloma [ 27 ], head and neck squamous cell carcinoma (HNSCC) [ 28 – 30 ], hepatocellular carcinoma (HCC) [ 31 ], neuroblastoma [ 32 ], non-small cell lung cancer (NSCLC) [ 33 – 35 ], and mesothelioma [ 36 ]. TLR3 ligands-mediated cell death is involved the formation of a signaling complex composed of TRIF, RIPK1, Fas-associated protein with death domain (FADD) and caspase-8, the death signaling complex also called ripoptosome [ 34 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, Smac mimetics have been reported to sensitize TLR3 ligands-induced apoptosis in some cancer cells [ 21 , 26 , 33 , 34 , 37 , 49 ]. Moreover, recent study has demonstrated that the removal of cellular FLICE-like inhibitory protein (c-FLIP), a strong negative regulator of caspase-8-mediated apoptosis could overcome the resistance to TLR3 ligands-mediated apoptosis [ 33 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

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Receptor-interacting protein kinase 1 is a key mediator in TLR3 ligand and Smac mimetic-induced cell death and suppresses TLR3 ligand-promoted invasion in cholangiocarcinoma

et al. 2020

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Background Toll-like receptor 3 (TLR3) ligand which activates TLR3 signaling induces both cancer cell death and activates anti-tumor immunity. However, TLR3 signaling can also harbor pro-tumorigenic consequences. Therefore, we examined the status of TLR3 in cholangiocarcinoma (CCA) cases to better understand TLR3 signaling and explore the potential therapeutic target in CCA. Methods The expression of TLR3 and receptor-interacting protein kinase 1 (RIPK1) in primary CCA tissues was assayed by Immunohistochemical staining and their associations with clinicopathological characteristics and survival data were evaluated. The effects of TLR3 ligand, Poly(I:C) and Smac mimetic, an IAP antagonist on CCA cell death and invasion were determined by cell death detection methods and Transwell invasion assay, respectively. Both genetic and pharmacological inhibition of RIPK1, RIPK3 and MLKL and inhibitors targeting NF-κB and MAPK signaling were used to investigate the underlying mechanisms. Results TLR3 was significantly higher expressed in tumor than adjacent normal tissues. We demonstrated in a panel of CCA cell lines that TLR3 was frequently expressed in CCA cell lines, but was not detected in a nontumor cholangiocyte. Subsequent in vitro study demonstrated that Poly(I:C) specifically induced CCA cell death, but only when cIAPs were removed by Smac mimetic. Cell death was also switched from apoptosis to necroptosis when caspases were inhibited in CCA cells-expressing RIPK3. In addition, RIPK1 was required for Poly(I:C) and Smac mimetic-induced apoptosis and necroptosis. Of particular interest, high TLR3 or low RIPK1 status in CCA patients was associated with more invasiveness. In vitro invasion demonstrated that Poly(I:C)-induced invasion through NF-κB and MAPK signaling. Furthermore, the loss of RIPK1 enhanced Poly(I:C)-induced invasion and ERK activation in vitro. Smac mimetic also reversed Poly(I:C)-induced invasion, partly mediated by RIPK1. Finally, a subgroup of patients with high TLR3 and high RIPK1 had a trend toward longer disease-free survival (p = 0.078, 28.0 months and 10.9 months). Conclusion RIPK1 plays a pivotal role in TLR3 ligand, Poly(I:C)-induced cell death when cIAPs activity was inhibited and loss of RIPK1 enhanced Poly(I:C)-induced invasion which was partially reversed by Smac mimetic. Our results suggested that TLR3 ligand in combination with Smac mimetic could provide therapeutic benefits to the patients with CCA. Graphical abstract

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Section: Discussionmentioning

confidence: 81%