RRC ID 34743
Author Kagawa Y, Matsumoto S, Kamioka Y, Mimori K, Naito Y, Ishii T, Okuzaki D, Nishida N, Maeda S, Naito A, Kikuta J, Nishikawa K, Nishimura J, Haraguchi N, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Ishii H, Doki Y, Matsuda M, Kikuchi A, Mori M, Ishii M.
Title Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo.
Journal PLoS One
Abstract The mechanism behind the spatiotemporal control of cancer cell dynamics and its possible association with cell proliferation has not been well established. By exploiting the intravital imaging technique, we found that cancer cell motility and invasive properties were closely associated with the cell cycle. In vivo inoculation of human colon cancer cells bearing fluorescence ubiquitination-based cell cycle indicator (Fucci) demonstrated an unexpected phenomenon: S/G2/M cells were more motile and invasive than G1 cells. Microarray analyses showed that Arhgap11a, an uncharacterized Rho GTPase-activating protein (RhoGAP), was expressed in a cell-cycle-dependent fashion. Expression of ARHGAP11A in cancer cells suppressed RhoA-dependent mechanisms, such as stress fiber formation and focal adhesion, which made the cells more prone to migrate. We also demonstrated that RhoA suppression by ARHGAP11A induced augmentation of relative Rac1 activity, leading to an increase in the invasive properties. RNAi-based inhibition of Arhgap11a reduced the invasion and in vivo expansion of cancers. Additionally, analysis of human specimens showed the significant up-regulation of Arhgap11a in colon cancers, which was correlated with clinical invasion status. The present study suggests that ARHGAP11A, a cell cycle-dependent RhoGAP, is a critical regulator of cancer cell mobility and is thus a promising therapeutic target in invasive cancers.
Volume 8(12)
Pages e83629
Published 2013-1-1
DOI 10.1371/journal.pone.0083629
PII PONE-D-13-35645
PMID 24386239
PMC PMC3875446
MeSH Cell Cycle* / genetics Cell Line, Tumor Cell Movement* / genetics Colorectal Neoplasms / genetics Colorectal Neoplasms / metabolism Colorectal Neoplasms / pathology Enzyme Activation GTPase-Activating Proteins / antagonists & inhibitors GTPase-Activating Proteins / genetics GTPase-Activating Proteins / metabolism* Gene Expression Gene Knockdown Techniques HCT116 Cells Humans Neoplasm Invasiveness Neoplasms / genetics Neoplasms / metabolism* Neoplasms / pathology*
IF 2.776
Times Cited 34
DNA material CSII-EF-MCS (RDB04378)