Enhanced intrinsic migration of aggressive breast cancer cells by inhibition of Rac1 GTPase

Zuo, Yufeng; Shields, Sarah-Kim; Chakraborty, Chandan

doi:10.1016/j.bbrc.2006.10.043

Cited by 45 publications

(39 citation statements)

References 26 publications

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“…In contrast, NSC23766 had little effect on the survival of the MCF12A normal mammary epithelial cells. Consistent with previous reports (36,41), NSC23766 selectively inhibited Rac1 activation without interfering with the activity of the closely related small GTPase Cdc42 in MDA-MB-231 (Fig. 1B) and other cell lines (data not shown).…”

Section: Resultssupporting

confidence: 92%

“…36). Repression of Rac1 activity by NSC23766 diminished Rac-dependent cell proliferation of PC3 prostate cancer line (36) and leukemia cell lines both in vitro and in vivo (37)(38)(39)(40); it also inhibited cell migration of several breast cancer cell lines (41) and induced apoptosis in leukemia (37)(38)(39)(40) and glioma (42) cell lines. Increasing evidence shows that Tiam1 and Trio are overexpressed in different types of human tumors (18)(19)(20), including human breast (42) carcinomas, which is believed to contribute to Rac1 hyperactivity.…”

Section: Introductionmentioning

confidence: 98%

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Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Yoshida

Zhang

Rosado

et al. 2010

Molecular Cancer Therapeutics

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Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epithelial cells. NSC23766 elicits its cytotoxicity via two distinct mechanisms in a cell line-dependent manner: induction of G 1 cell cycle arrest in cell lines (MDA-MB-231, MCF7, and T47D) that express retinoblastoma (Rb) protein or apoptosis in Rb-deficient MDA-MB-468 cells. In MDA-MB-231 cells, Rac1 inhibition induced G 1 cell cycle arrest through downregulation of cyclin D1 and subsequent dephosphorylation/inactivation of Rb. By contrast, MDA-MB-468 cells underwent substantial apoptosis that was associated with loss of antiapoptotic proteins survivin and X-linked inhibitor of apoptosis protein (XIAP). Rac1 knockdown by RNAi interference confirmed the specificity of NSC23766 and requirement for Rac1 in the regulation of cyclin D1, survivin, and XIAP in breast cancer cells. Further, NF-κB, but not c-Jun NH 2 -terminal kinase or p38 pathways, mediates the survival signal from Rac1. Overall, our results indicate that Rac1 plays a central role in breast cancer cell survival through regulation of NF-κB-dependent gene products. Mol Cancer Ther; 9(6); 1657-68. ©2010 AACR.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Yoshida

Zhang

Rosado

et al. 2010

Molecular Cancer Therapeutics

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“…4B) demonstrated that hESCs pretreated with 100 M Y27632 displayed a Ϸ2-fold increase in wound closure compared with control untreated hESCs. In contrast, and as shown for other cell types (20), inhibition of Rac1 signaling with the Rac1 inhibitor, NSC23766 (21) resulted in a significant decrease in cell motility (Fig. 4 C and D).…”

Section: Inhibition Of Rho-kinase Signaling In Hescs Increases Trophosupporting

confidence: 73%

Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

Grewal

Carver

Ridley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

167

140

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Failure of the human embryo to implant into the uterine wall during the early stages of pregnancy is a major cause of infertility. Implantation involves embryo apposition and adhesion to the endometrial epithelium followed by penetration through the epithelium and invasion of the embryonic trophoblast through the endometrial stroma. Although gene-knockdown studies have highlighted several molecules that are important for implantation in the mouse, the molecular mechanisms controlling implantation in the human are unknown. Here, we demonstrate in an in vitro model for human implantation that the Rho GTPases Rac1 and RhoA in human endometrial stromal cells modulate invasion of the human embryo through the endometrial stroma. We show that knockdown of Rac1 expression in human endometrial stromal cells inhibits human embryonic trophoblast invasion into stromal cell monolayers, whereas inhibition of RhoA activity promotes embryo invasion. Furthermore, we demonstrate that Rac1 is required for human endometrial stromal cell migration and that the motility of the stromal cells increases at implantation sites. This increased motility correlates with a localized increase in Rac1 activation and a reciprocal decrease in RacGAP1 levels. These results reveal embryo-induced and localized endometrial responses that may govern implantation of the human embryo.human trophoblast invasion ͉ implantation in vitro ͉ Rac-1 activation ͉ RacGAP1 ͉ Rho GTPases

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“…For example, inhibition of Rac1 blocks migration in some breast cancer lines, but stimulates it in others (Zuo et al, 2006). Within a single cell line, Rac activation can increase or decrease migration, depending on the substrate (Sander et al, 1998).…”

Section: Context-dependent and Paradoxical Functionsmentioning

confidence: 99%

Control of gastrula cell motility by the Goosecoid/Mix.1/ Siamois network: Basic patterns and paradoxical effects

Luu

Nagel

Wacker

et al. 2008

Developmental Dynamics

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In the vegetal half of the Xenopus gastrula, cell populations differ with respect to migration on fibronectin substratum. We show that the paired-class homeodomain transcription factors Goosecoid (Gsc), Mix.1, and Siamois (Sia) are involved in the modulation of migration velocity and cell polarity. Mix.1 is expressed in the whole vegetal half and serves as a competence factor that is necessary, but not sufficient, for rapid cell migration and polarization.

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Enhanced intrinsic migration of aggressive breast cancer cells by inhibition of Rac1 GTPase

Cited by 45 publications

References 26 publications

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration

Control of gastrula cell motility by the Goosecoid/Mix.1/ Siamois network: Basic patterns and paradoxical effects

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