Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo

• Published in: PloS one 2013-12, Vol.8 (12), p.e83629-e83629
• Main Authors: Kagawa, Yoshinori, Matsumoto, Shinji, Kamioka, Yuji, Mimori, Koshi, Naito, Yoko, Ishii, Taeko, Okuzaki, Daisuke, Nishida, Naohiro, Maeda, Sakae, Naito, Atsushi, Kikuta, Junichi, Nishikawa, Keizo, Nishimura, Junichi, Haraguchi, Naotsugu, Takemasa, Ichiro, Mizushima, Tsunekazu, Ikeda, Masataka, Yamamoto, Hirofumi, Sekimoto, Mitsugu, Ishii, Hideshi, Doki, Yuichiro, Matsuda, Michiyuki, Kikuchi, Akira, Mori, Masaki, Ishii, Masaru
• Format: Article
• Language: English
• Subjects: Augmentation; Biochemistry; Biology; Cancer; Cell cycle; Cell Cycle - genetics; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell proliferation; Colon; Colon cancer; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA microarrays; Enzyme Activation; Fluorescence; Gene Expression; Gene Knockdown Techniques; GTPase-activating protein; GTPase-Activating Proteins - antagonists & inhibitors; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Guanosine triphosphatases; HCT116 Cells; Humans; Immunology; Inoculation; Invasiveness; Kinases; Laboratories; Lasers; M cells; Medicine; Microscopy; Molecular biology; Motility; Neoplasm Invasiveness; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Proteins; Quarks; Rac1 protein; RhoA protein; RNA-mediated interference; Surgery; Ubiquitin; Ubiquitination
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0083629

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.