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Dominant‐negative Rac increases both inherent and ionizing radiation‐induced cell migration in C6 rat glioma cells
Author(s) -
Hwang SoYoung,
Jung JaeWon,
Jeong JaeSeob,
Kim YunJung,
Oh EokSoo,
Kim TaeHyun,
Kim JooYoung,
Cho KwanHo,
Han InnOc
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21574
Subject(s) - cell migration , rhoa , focal adhesion , cdc42 , microbiology and biotechnology , rac gtp binding proteins , paxillin , rac1 , stress fiber , kinase , cancer research , p38 mitogen activated protein kinases , biology , signal transduction , chemistry , cell , protein kinase a , biochemistry
Abstract Rho‐like GTPases, including Cdc42, Rac1 and RhoA, regulate distinct actin cytoskeleton changes required for cell adhesion, migration and invasion. In the present study, we examined the role of Rac signaling in inherent migration, as well as radiation‐induced migration, of rat glioma cells. Stable overexpression of dominant‐negative Rac1N17 in a C6 rat glioma cell line (C6‐RacN17) promoted cell migration, and ionizing radiation further increased this migration. Migration was accompanied by decreased expression of the focal adhesion molecules FAK and paxillin. Focal contacts and actin stress fibers were also reduced in C6‐RacN17 cells. Downstream effectors of Rac include JNK and p38 MAP kinases. Irradiation transiently activated p38, JNK and ERK1/2 MAP kinases in C6‐RacN17 cells, while p38 and JNK were constitutively activated in C6 control cells. Blocking JNK activity with JNK inhibitor SP600125 inhibited migration, suggesting that the JNK pathway may regulate radiation‐induced, as well as inherent, migration of C6‐RacN17 cells. Additionally, the radiation‐induced migration increase was also inhibited by SB203580, a specific inhibitor of p38 MAP kinase. However, PD98059, a MEK kinase 1 inhibitor, failed to influence migration. This is the first evidence that suppression of Rac signaling may be involved in invasion or metastasis of glioma cells before and/or after radiotherapy. These data further suggest that radiotherapy for malignant glioma needs to be used with caution because of the potential for therapy‐induced cell migration or invasion and that pharmacological inhibition of cell migration and invasion through targeting the Rac signaling pathway may represent a new approach for improving the therapeutic efficacy of radiotherapy for malignant glioma. © 2005 Wiley‐Liss, Inc.