Lung Cancer Cells That Survive Ionizing Radiation Show Increased Integrin alpha 2 beta 1-and EGFR-Dependent Invasiveness

Li Xue; Ishihara Seiichiro; Yasuda Motoaki; Nishioka Takeshi; Mizutani Takeomi; Ishikawa Masayori; Kawabata Kazushige; Shirato Hiroki; Haga Hisashi

タイトル	en Lung Cancer Cells That Survive Ionizing Radiation Show Increased Integrin alpha 2 beta 1-and EGFR-Dependent Invasiveness
作成者	en Li, Xue en Ishihara, Seiichiro en Yasuda, Motoaki NRID 1000090239765 en Nishioka, Takeshi NRID 1000080271659 en Mizutani, Takeomi en Ishikawa, Masayori en Kawabata, Kazushige NRID 1000020261274 en Shirato, Hiroki NRID 1000020187537 en Haga, Hisashi NRID 1000000292045
アクセス権	open access
権利情報	http://creativecommons.org/licenses/by/3.0/ en Creative Commons Attribution 3.0 Unported
主題	NDC 490
内容注記	Abstract en Ionizing radiation (IR)-enhanced tumor invasiveness is emerging as a contributor to the limited benefit of radiotherapy; however, its mechanism is still unclear. We previously showed that subcloned lung adenocarcinoma A549 cells (P cells), which survived 10 Gy IR (IR cells), acquired high invasiveness in vitro. Here, we tried to identify the mechanism by which IR cells increase their invasiveness by examining altered gene expression and signaling pathways in IR cells compared with those in P cells. To simulate the microenvironment in vivo, cells were embedded in a three-dimensional (3D) collagen type I gel, in which the IR cells were elongated, while the P cells were spherical. The integrin expression pattern was surveyed, and expression levels of the integrin alpha 2 and beta 1 subunits were significantly elevated in IR cells. Knockdown of alpha 2 expression or functional blockade of integrin alpha 2 beta 1 resulted in a round morphology of IR cells, and abrogated their invasion in the collagen matrix, suggesting the molecule's essential role in cell spread and invasion in 3D collagen. Epidermal growth factor receptor (EGFR) also presented enhanced expression and activation in IR cells. Treatment with EGFR tyrosine kinase inhibitor, PD168393, decreased the ratio of elongated cells and cell invasiveness. Signaling molecules, including extracellular signal-regulated kinase-1/2 (Erk1/2) and Akt, exhibited higher activation in IR cells. Inhibition of Akt activation by treating with phosphoinositide 3-kinase (PI3K) inhibitor LY294002 decreased IR cell invasion, whereas inhibition of Erk1/2 activation by mitogen-activated protein kinase kinase (MEK) inhibitor U0126 did not. Our results show that integrin alpha 2 beta 1 and EGFR cooperatively promote higher invasiveness of IR-survived lung cancer cells, mediated in part by the PI3K/Akt signaling pathway, and might serve as alternative targets in combination with radiotherapy.
出版者	en Public library science
日付	Issued2013-08-08
言語	eng
資源タイプ	journal article
出版タイプ	VoR
資源識別子	HDL http://hdl.handle.net/2115/53355
関連	isIdenticalTo DOI https://doi.org/10.1371/journal.pone.0070905
収録誌情報	PISSN 1932-6203 en Plos one 巻8 号8 開始ページe70905
ファイル	fulltext journal.pone.0070905.pdf 5.26 MB (application/pdf) Issued2013-08-08
コンテンツ更新日時	2023-07-26