Identification of Integrin β1 as a Novel PAG1-Interacting Protein Involved in the Inherent Radioresistance of Human Laryngeal Carcinoma

Abstract

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.

Synergistic Radiosensitization by Gold Nanoparticles and the Histone Deacetylase Inhibitor SAHA in 2D and 3D Cancer Cell Cultures

“…These drawbacks encompass inherent or acquired radioresistance which is frequently observed in certain breast, non-small cell lung and androgen-independent prostate cancers. To overcome such radioresistance an increased irradiation dose should be applied, ultimately leading to the undesired consequences of damaging healthy organs and tissues in the anatomical proximity of the targeted tumor [63][64][65][66][67][68]. Therefore, in recent years great impetus has been gained in developing and optimizing various types of materials for radiation-enhancing purposes in order to avoid the employment of excessisve radiation doses to eradicate cancer and simultaniously to protect healthy tissues.…”

Role of Integrins in Resistance to Therapies Targeting Growth Factor Receptors in Cancer

“…In cancer cells, β1 integrins are associated with proliferative signaling, trigger cell death resistance, induce angiogenesis and activate cell migration and the metastatic cascade [35,36,37,38,39]. β1 integrins contribute to chemotherapy resistance [38,40,41,42,43,44,45,46,47,48,49,50] and promote radiotherapy resistance in HNSCC [51,52,53,54], breast carcinoma [55,56], laryngeal carcinoma [57,58], and glioma [59,60]. Based on these observations, β1 integrin antagonists such as small molecules (ATN-161, JSM6427) or function-blocking antibodies (volociximab, OS2966) have been considered as potential therapeutic approaches [32].…”

Effect of combination of curcumin and GLUT‐1 AS‐ODN on radiosensitivity of laryngeal carcinoma through regulating autophagy

“…1 There are many evidences that multiple molecular and cellular processes are involved in the development of radioresistance formation. [2][3][4][5] Among that, intracellular autophagy flux is proved of great importance in radioresistance of some human solid cancers and autophagy modulation may enhance the radiosensitivity of several cancer types. [6][7][8] However, the association of autophagy process and radioresistance in laryngeal cancer remains unclear.…”

“…Radioresistance can cause treatment failure, occurrence, metastasis and is a major limitation in the process of radiotherapy management with laryngeal carcinoma patients 1 . There are many evidences that multiple molecular and cellular processes are involved in the development of radioresistance formation 2‐5 . Among that, intracellular autophagy flux is proved of great importance in radioresistance of some human solid cancers and autophagy modulation may enhance the radiosensitivity of several cancer types 6‐8 .…”