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Cell Death Dis. 2018 Aug 29;9(9):874. doi: 10.1038/s41419-018-0850-0.

Release of c-FLIP brake selectively sensitizes human cancer cells to TLR3-mediated apoptosis.

Author information

1
Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, F-69373, Lyon, France.
2
Univ Lyon, Université Claude Bernard Lyon 1, Faculté d'Odontologie, Hospices Civils de Lyon, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, F-69373, Lyon, France.
3
Département de Biopathologie - Registre MESONAT, Centre Léon Bérard, 69008 Lyon, U1086 INSERM-UCBN « Cancer & Prévention », Caen, France.
4
Département de Biopathologie, Centre Léon Bérard, 69008 Lyon, INSERM U823, Institut A. Bonniot, 38700, La Tronche, France.
5
Univ. Bourgogne Franche-Comté, INSERM, LNC UMR866, F-21000, Dijon, France.
6
Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Service d'Anatomie Pathologique, 69495, Pierre Bénite Cedex, France.
7
Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, F-69373, Lyon, France. yestornes@gmail.com.

Abstract

Toll-like receptor 3 (TLR3) mediates innate immune responses by sensing viral dsRNA, but also induces apoptosis selectively in cancer cells. Our analysis by immunohistochemistry revealed that TLR3 is frequently overexpressed in 130 non-small cell lung cancer (NSCLC) patients' samples compared with normal bronchial epithelium (P < 0.0001, Mann-Whitney test), supporting the therapeutic potential of TLR3 ligand for this type of cancer. However, a proportion of TLR3-expressing cancer cell lines, including NSCLC, remain resistant to TLR3-mediated apoptosis, and the underlying mechanism of resistance remains unclear. We here investigated the molecular basis conferring resistance to non-transformed vs. transformed cells against TLR3-mediated cell death. In non-transformed epithelial cells cellular FLICE-like inhibitory protein (c-FLIP) and cellular Inhibitor of APoptosis (cIAPs) ubiquitin ligases exerted an efficient double brake on apoptosis signaling. In contrast, releasing only one of these two brakes was sufficient to overcome the resistance of 8/8 cancer cell lines tested. Remarkably, the release of the c-FLIP, but not cIAPs, brake only results in the sensitization of all human cancer cells to TLR3-mediated apoptosis. Taking advantage of the difference between transformed and non-transformed cells, we developed a rational strategy by combining the chemotherapeutic agent paclitaxel, which decreases c-FLIP expression, with TLR3 ligand. This combination was highly synergistic for triggering apoptosis in cancer cells but not in non-transformed cells. In vivo, the combination of paclitaxel with dsRNA delayed tumor growth and prolonged survival in a mouse xenograft lung tumor model. In conclusion, combining the release of the c-FLIP brake with TLR3 ligand synergizes to selectively kill cancer cells, and could represent an efficient and safe therapy against TLR3-expressing cancers such as NSCLC.

PMID:
30158588
PMCID:
PMC6115461
DOI:
10.1038/s41419-018-0850-0
[Indexed for MEDLINE]
Free PMC Article

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