J Cancer 2018; 9(22):4128-4138. doi:10.7150/jca.26885 This issue
1. Department of pharmacology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
2. Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
Inherent radioresistance plays a crucial role in the failure of radiotherapy. Using the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2min) cell lines established from the parental cell line Hep-2, we previously reported that phosphoprotein associated with glycosphingolipid-enriched microdomains 1(PAG1) overexpression in laryngeal carcinoma cells was correlated with inherent radioresistant phenotypes. However, the underlying mechanisms of this effect remain unknown. In the present study, we performed a proteomic screen to investigate the interactome of PAG1 in Hep-2max cells resulting in the identification of several interaction partners. Bioinformatic analysis and immunofluorescence experiments indicated the integrin β1 to be a crucial interaction partner of PAG1. PAG1 was also highly expressed in laryngeal carcinoma radioresistant tissues and showed co-localization with integrin β1. In addition, we demonstrated that integrin β1's binding to PAG1 could be interrupted by MβCD, an inhibitor of lipid rafts formation. Moreover, knockdown of integrin β1 by RNA interference sensitized radioresistant cells to irradiation. Importantly, we identified 2 potential interaction sites (Pro216-Arg232 and Asn356-Gly377) in the cytoplasmic domain of PAG1 using high throughput peptide arrays. Taken together, these results suggest that the binding of PAG1 to integrin β1 in lipid rafts is essential for inherent radioresistance of human laryngeal carcinoma.
Keywords: PAG1, integrin β1, inherent radioresistance, laryngeal carcinoma, interaction partner