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

Cell Death & Disease
Lugain AlkurdiYann Estornes

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 adva...Continue Reading

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Citations

Feb 26, 2020·International Journal of Molecular Sciences·Francesca BianchiLucia Sfondrini
May 30, 2020·International Journal of Molecular Sciences·Christian Sordo-BahamondeAlejandro López-Soto
Jun 14, 2019·Journal of Dental Research·F L WuX J Wang
Nov 6, 2020·Cancers·Ximena Maria MuresanKarel Souček
Jan 20, 2022·Apoptosis : an International Journal on Programmed Cell Death·Manuel Nico DoldArnim Weber

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Methods Mentioned

BETA
flow cytometry
transfection
ELISA
xenograft
xenografts
Assay
surgical resection

Software Mentioned

CellQuest
Histolab

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