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

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 IshiiYuichiro Doki, Michiyuki Matsuda, Akira Kikuchi, Masaki Mori, Masaru Ishii

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Article numbere83629
JournalPloS one
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 30 2013

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rho GTP-Binding Proteins
cell invasion
guanosinetriphosphatase
cell movement
Cell Movement
cell cycle
Cell Cycle
Cells
GTPase-activating proteins
Neoplasms
colorectal neoplasms
Colonic Neoplasms
neoplasms
cells
Stress Fibers
Bearings (structural)
adhesion
Focal Adhesions
cell proliferation
Ubiquitination

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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

In: PloS one, Vol. 8, No. 12, e83629, 30.12.2013.

Research output: Contribution to journalArticle

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 2013, 'Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo', PloS one, vol. 8, no. 12, e83629. https://doi.org/10.1371/journal.pone.0083629
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. / Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo. In: PloS one. 2013 ; Vol. 8, No. 12.
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AU - Naito, Yoko

AU - Ishii, Taeko

AU - Okuzaki, Daisuke

AU - Nishida, Naohiro

AU - Maeda, Sakae

AU - Naito, Atsushi

AU - Kikuta, Junichi

AU - Nishikawa, Keizo

AU - Nishimura, Junichi

AU - Haraguchi, Naotsugu

AU - Takemasa, Ichiro

AU - Mizushima, Tsunekazu

AU - Ikeda, Masataka

AU - Yamamoto, Hirofumi

AU - Sekimoto, Mitsugu

AU - Ishii, Hideshi

AU - Doki, Yuichiro

AU - Matsuda, Michiyuki

AU - Kikuchi, Akira

AU - Mori, Masaki

AU - Ishii, Masaru

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