title: Defective NF-κB signaling in metastatic head and neck cancer cells leads to enhanced apoptosis by double-stranded RNA.
abstract: Ligands to several Toll-like receptors (TLR), which mediate innate immune responses and chronic inflammation have been used as adjuvants to immunotherapy to enhance their antitumor activity. In particular, double-stranded RNAs that are cognate ligands of TLR3 have been used to trigger proapoptotic activity in cancer cells. However, a mechanistic understanding of TLR3-mediated apoptosis and its potential involvement in controlling tumor metastasis has been lacking. In this study, we used paired cell lines and fresh tumor specimens, derived from autologous primary and metastatic head and neck squamous cell carcinoma, to investigate the role of TLR3 signaling in metastatic progression. Compared with primary tumor cells, metastatic tumor cells were highly sensitive to TLR3-mediated apoptosis after double-stranded RNA treatment. Enhanced apoptosis in metastatic cells was dependent on double-stranded RNA and TLR3 and also the TLR3 effector signaling protein TRIF. Downstream responses requiring NF-κB were critical for apoptosis in metastatic cells, the defects in which could be resuscitated by alternative pathways of NF-κB activation. By elucidating how TLR3 ligands trigger apoptosis in metastatic cells, our findings suggest insights into how to improve their clinical use.
authors: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors: Naoki
authors: N
authors: Umemura
authors: Jianzhong
authors: J
authors: Zhu
authors: Yvonne K
authors: YK
authors: Mburu
authors: Adriana
authors: A
authors: Forero
authors: Paishiun N
authors: PN
authors: Hsieh
authors: Ravikumar
authors: R
authors: Muthuswamy
authors: Pawel
authors: P
authors: Kalinski
authors: Robert L
authors: RL
authors: Ferris
authors: Saumendra N
authors: SN
authors: Sarkar
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3