Journal
JOURNAL OF CANCER
Volume 9, Issue 22, Pages 4128-4138Publisher
IVYSPRING INT PUBL
DOI: 10.7150/jca.26885
Keywords
PAG1; integrin beta 1; inherent radioresistance; laryngeal carcinoma; interaction partner
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Funding
- National Natural Science Foundation of China [81502666]
- Initial Project for Post-Graduates of Hubei University of Medicine [2016QDJZR10]
- Natural Science Foundation of Hubei Province [2015CFA076]
- Free Exploration Foundation of Hubei University of Medicine [FDFR201802]
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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 beta 1 to be a crucial interaction partner of PAG1. PAG1 was also highly expressed in laryngeal carcinoma radioresistant tissues and showed co-localization with integrin beta 1. In addition, we demonstrated that integrin beta 1's binding to PAG1 could be interrupted by MBCD, an inhibitor of lipid rafts formation. Moreover, knockdown of integrin beta 1 by RNA interference sensitized radioresistant cells to irradiation. Importantly, we identified 2 potential interaction sites (Pro(216)-Arg(232) and Asn(356) -Gly(337)) in the cytoplasmic domain of PAG1 using high throughput peptide arrays. Taken together, these results suggest that the binding of PAG1 to integrin beta 1 in lipid rafts is essential for inherent radioresistance of human laryngeal carcinoma.
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