Dominant-negative Rac increases both inherent and ionizing radiation-induced cell migration in C6 rat glioma cells.
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.
Hwang
So-Young
SY
Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
Jung
Jae-Won
JW
Jeong
Jae-Seob
JS
Kim
Yun-Jung
YJ
Oh
Eok-Soo
ES
Kim
Tae-Hyun
TH
Kim
Joo-Young
JY
Cho
Kwan-Ho
KH
Han
Inn-Oc
IO
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D002465:Cell Movement / Q000528:radiation effects*; D005910:Glioma / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics* / Q000502:physiology
D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020744:rac GTP-Binding Proteins