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Abstract
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.

Affiliations

A-Ram Kang  1 , Jeong Hyun Cho  1 , Na-Gyeong Lee  1 , Jie-Young Song  1 , Sang-Gu Hwang  1 , Dae-Hee Lee  2 , Hong-Duck Um  1 , Jong Kuk Park  1
1 Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Korea.
2 Department of Marine Food Science and Technology, Gangneung-Wonju National University, 120 Gangneung, Gangwon 210-702, Korea.