Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma.

ABSTRACT: BACKGROUND:The epidermal growth factor receptor (EGFR)-targeted therapies have been tested in the clinic as treatments for head and neck squamous cell carcinoma (HNSCC). Owing to intrinsic or acquired resistance, EGFR-targeted therapies often lead to a low response rate and treatment failure. Interferon-alpha (IFN?) is a chemosensitising agent and multi-functional cytokine with a tumour inhibitory effect. However, the synergic effect of IFN? and EGFR-targeted therapies (erlotinib and nimotuzumab) and their mechanisms in HNSCC remain unclear. METHODS:The interactions between IFN?, erlotinib, and nimotuzumab were evaluated in vitro in HNSCC cells. The synergistic effect of IFN? (20?000?IU per day, s.c.), erlotinib (50?mg?kg-1 per day, i.g.) and nimotuzumab (10?mg?kg-1 per day, i.p.) was further confirmed in vivo using HNSCC xenografts in nude mice. The upregulation of retinoic-acid inducible gene I (RIG-I) induced by IFN? and EGFR-targeted therapies and its mechanism were detected in vitro and in vivo. RESULTS:IFN? enhances the antitumour effects of erlotinib and nimotuzumab on HNSCC cells both in vitro and in vivo. Importantly, both IFN? and EGFR-targeted therapies promote the expression of RIG-I by activating signal transducers and activators of transcription 1 (STAT1) in HNSCC cells. RIG-I knockdown reduced the sensitivity of HN4 and HN30 cells to IFN?, erlotinib, and nimotuzumab. Moreover, IFN? transcriptionally induced RIG-I expression in HNSCC cells through STAT1. CONCLUSIONS:IFN? enhances the effect of EGFR-targeted therapies by upregulating RIG-I, and its expression may represent a predictor of the effectiveness of a combination treatment including IFN? in HNSCC.

SUBMITTER: Ma H 

PROVIDER: S-EPMC5830595 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature