RIP1 Is a Novel Component of γ-ionizing Radiation-Induced Invasion of Non-Small Cell Lung Cancer Cells

International Journal of Molecular Sciences

Dae-Hee Lee¹  Sang-Gu Hwang²  Jeong Hyun Cho²  Na-Gyeong Lee²  A-Ram Kang²  Jong Kuk Park²  Hong-Duck Um²  Jie-Young Song² 

[1] Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Korea;Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea;

关键词: signal transduction;    γ-ionizing radiation;    non-small cell lung cancer;    cancer invasion;    epithelial-mesenchymal transition;    tumor microenvironment;   

DOI  :  10.3390/ijms21134584

来源: DOAJ

【 摘 要 】

Abstract: Previously, we demonstrated that γ-ionizing radiation (IR) triggers the invasion/migration of A549 cells via activation of an EGFR–p38/ERK–STAT3/CREB-1–EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in γ-ionizing radiation (IR)-induced migration/invasion. Expression of receptor-interacting protein (RIP) 1 was initially increased upon exposure of A549, a non-small cell lung cancer (NSCLC) cell line, to IR. IR-induced RIP1 is located downstream of EGFR and involved in the expression/activity of matrix metalloproteases (MMP-2 and MMP-9) and vimentin, suggesting a role in epithelial-mesenchymal transition (EMT). Our experiments showed that IR-induced RIP1 sequentially induces Src-STAT3-EMT to promote invasion/migration. Inhibition of RIP1 kinase activity and expression blocked induction of EMT by IR and suppressed the levels and activities of MMP-2, MMP-9 and vimentin. IR-induced RIP1 activation was additionally associated with stimulation of the transcriptional factor NF-κB. Specifically, exposure to IR triggered NF-κB activation and inhibition of NF-κB suppressed IR-induced RIP1 expression, followed by a decrease in invasion/migration as well as EMT. Based on the collective results, we propose that IR concomitantly activates EGFR and NF-κB and subsequently triggers the RIP1–Src/STAT3–EMT pathway, ultimately promoting metastasis.

【 授权许可】

Unknown