Targeting human epidermal growth factor receptor 2 enhances radiosensitivity and reduces the metastatic potential of Lewis lung carcinoma cells
Journal
Radiation Oncology
Journal Volume
15
Journal Issue
1
Date Issued
2020
Author(s)
Abstract
Background: Sublethal radiation induces matrix metalloproteinase 9 (MMP-9)-mediated radioresistance in Lewis lung carcinoma (LLC) cells and their metastatic dissemination. We aim to determine if EGFR/HER2 activation associates with MMP-9-mediated radioresistance and invasiveness in irradiated LLC cells. Methods: LLC cells were treated with erlotinib or afatinib followed by sublethal radiation. After irradiation, we examined the phosphorylation of EGFR/HER2 and MMP-9 expression. Colony formation assay determined if the kinase inhibitors sensitize LLC cells to radiation. Matrigel-coated Boyden chamber assay assessed cellular invasiveness. Resulting tumors of wild-type LLC cells or HER2 knock-down mutant cells were irradiated to induce pulmonary metastases. Results: Afatinib more effectively sensitized LLC cells to radiation and decreased invasiveness by inhibiting phosphorylation of EGFR, HER2, Akt, ERK, and p38, and down-regulating MMP-9 when compared to erlotinib. Afatinib abolished radiation-induced lung metastases in vivo. Furthermore, LLC HER2 knock-down cells treated with radiation had growth inhibition. Conclusion: Dual inhibition of radiation-activated EGFR and HER2 signaling by afatinib suppressed the proliferation and invasion of irradiated LLC cells. Increased radiosensitivity and decreased metastatic dissemination were observed by pharmacological or genetic HER2 inhibition in vivo. These findings indicate that HER2 plays a pivotal role in enhancing radioresistance and reducing metastatic potential of LLC cells. ? 2020 The Author(s).
SDGs
Other Subjects
afatinib; epidermal growth factor receptor 2; erlotinib; gelatinase B; matrigel; protein kinase B; synaptophysin; afatinib; epidermal growth factor receptor; epidermal growth factor receptor 2; ERBB2 protein, human; gelatinase B; animal cell; animal experiment; animal model; animal tissue; Article; cancer inhibition; cell invasion; colony formation; controlled study; down regulation; drug effect; enzyme activation; enzyme inhibition; human; in vivo study; Lewis carcinoma; Lewis lung carcinoma cell line; lung metastasis; lung metastasis cell line; male; mouse; nonhuman; protein expression; protein phosphorylation; radiosensitivity; signal transduction; transwell assay; animal; C57BL mouse; drug effect; Lewis carcinoma; metastasis; pathology; phosphorylation; physiology; radiation tolerance; tumor cell line; tumor invasion; Afatinib; Animals; Carcinoma, Lewis Lung; Cell Line, Tumor; ErbB Receptors; Humans; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Radiation Tolerance; Receptor, ErbB-2; Signal Transduction
Publisher
BioMed Central Ltd.
Type
journal article