Cell Cycle-Dependent Rho GTPase Activity Dynamically Regulates Cancer Cell Motility and Invasion In Vivo
Year: 2013
Type: article
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.
Source: PLoS ONE
Authors: Yoshinori Kagawa, Shinji Matsumoto, Yuji Kamioka, Koshi Mimori, Yoko Naito, Taeko Ishii, Daisuke Okuzaki, Naohiro Nishida, Sakae Maeda, Atsushi Naito, Junichi Kikuta, Keizo Nishikawa, Junichi Nishimura, Naotsugu Haraguchi, Ichiro Takemasa, Tsunekazu Mizushima, Masataka Ikeda, Hirofumi Yamamoto, Mitsugu Sekimoto, Hideshi Ishii, Yuichiro Doki, Michiyuki Matsuda, Akira Kikuchi, Masaki Mori, Masaru Ishii
Institutions: Japan Science and Technology Agency, Immunology Frontier Research Center, The University of Osaka, The University of Osaka, Kyoto University, Medical Institute of Bioregulation, Kyushu University, Research Institute for Microbial Diseases, The University of Osaka, Kyushu University Beppu Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Awards: G4083463131, The pathophysiology of rheumatoid arthritis elucidated by intravital multiphoton imaging, Wnt signaling promotes epithelial tubulogenesis through the regulation of cell morphology and proliferation, Functional intravital imaging of the breast tumor invasion process in tumor microenvironment, G7716933661, Development of novel methods for evaluating RA pathogenesis and activity
OpenAlex ID: W1990905635