Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

RIP1 is Novel Component of γ-Ionizing Radiation-Induced Invasion of Non-Small Cell Lung Cancer Cells

Version 1 : Received: 21 January 2020 / Approved: 22 January 2020 / Online: 22 January 2020 (03:04:00 CET)

How to cite: Cho, J.H.; Kang, A.; Lee, N.; Song, J.; Hwang, S.; Lee, D.; Um, H.; Park, J.K. RIP1 is Novel Component of γ-Ionizing Radiation-Induced Invasion of Non-Small Cell Lung Cancer Cells. Preprints 2020, 2020010252 (doi: 10.20944/preprints202001.0252.v1). Cho, J.H.; Kang, A.; Lee, N.; Song, J.; Hwang, S.; Lee, D.; Um, H.; Park, J.K. RIP1 is Novel Component of γ-Ionizing Radiation-Induced Invasion of Non-Small Cell Lung Cancer Cells. Preprints 2020, 2020010252 (doi: 10.20944/preprints202001.0252.v1).

Abstract

Previously, we demonstrated that 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.

Subject Areas

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

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