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

Previously, we demonstrated that &gamma
ionizing radiation (IR) triggers the invasion/migration of A549 cells via activation of an EGFR&ndash
p38/ERK&ndash
STAT3/CREB-1&ndash
EMT pathway. Here, we have demonstrated the involvement of a novel intracellular signaling mechanism in &gamma
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-&kappa
B. Specifically, exposure to IR triggered NF-&kappa
B activation and inhibition of NF-&kappa
B 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-&kappa
B and subsequently triggers the RIP1&ndash
Src/STAT3&ndash
EMT pathway, ultimately promoting metastasis.