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

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Title: Lung Cancer Cells That Survive Ionizing Radiation Show Increased Integrin alpha 2 beta 1-and EGFR-Dependent Invasiveness
Authors: Li, Xue Browse this author
Ishihara, Seiichiro Browse this author
Yasuda, Motoaki Browse this author →KAKEN DB
Nishioka, Takeshi Browse this author →KAKEN DB
Mizutani, Takeomi Browse this author
Ishikawa, Masayori Browse this author
Kawabata, Kazushige Browse this author →KAKEN DB
Shirato, Hiroki Browse this author →KAKEN DB
Haga, Hisashi Browse this author →KAKEN DB
Issue Date: 8-Aug-2013
Publisher: Public library science
Journal Title: Plos one
Volume: 8
Issue: 8
Publisher DOI: 10.1371/journal.pone.0070905
Abstract: 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.
Type: article
Appears in Collections:生命科学院・先端生命科学研究院 (Graduate School of Life Science / Faculty of Advanced Life Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 芳賀 永

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