Rac signaling in tumorigenesis and as target for anticancer drug development

Sun, Di; Xu, Duo; Zhang, Baolin

doi:10.1016/j.drup.2006.12.001

Cited by 50 publications

(54 citation statements)

References 161 publications

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“…Rac1 is essential for normal cell function and, when improperly activated, contributes to tumor cell growth, invasion, and angiogenesis (35). In breast cancer cells, the aberrant Rac1 activity has been related to the elevated expression of its GEF proteins, such as Tiam1 and Trio.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…Rac1 and its signaling components have thus been proposed as a therapeutic target for treating human cancers (reviewed in ref. 35).…”

Section: Introductionmentioning

confidence: 99%

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 gene is a member of the monomeric G-protein, Rho GTPases family member. It plays crucial roles in signal transduction pathway that control proliferation, adhesion, and migration of cells during embryonic development, invasiveness of tumour cells (Jin et al, 2007) as well as apoptosis (Sun et al, 2006). The expression of RAC1 is important for cell growth, motility and morphology in glioma cells (Hu et al, 2009;Moniz et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

Haris

Ismail²,

Idris³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Glioblastoma, the most aggressive and malignant form of glioma, appears to be resistant to various chemotherapeutic agents. Hence, approaches have been intensively investigated to targeti specific molecular pathways involved in glioblastoma development and progression. Aloe emodin is believed to modulate the expression of several genes in cancer cells. We aimed to understand the molecular mechanisms underlying the therapeutic effect of Aloe emodin on gene expression profiles in the human U87 glioblastoma cell line utilizing microarray technology. The gene expression analysis revealed that a total of 8,226 gene alterations out of 28,869 genes were detected after treatment with 58.6 µg/ml for 24 hours. Out of this total, 34 genes demonstrated statistically significant change (p<0.05) ranging from 1.07 to 1.87 fold. The results revealed that 22 genes were up-regulated and 12 genes were down-regulated in response to Aloe emodin treatment. These genes were then grouped into several clusters based on their biological functions, revealing induction of expression of genes involved in apoptosis (programmed cell death) and tissue remodelling in U87 cells (p<0.01). Several genes with significant changes of the expression level e.g. SHARPIN, BCAP31, FIS1, RAC1 and TGM2 from the apoptotic cluster were confirmed by quantitative real-time PCR (qRT-PCR). These results could serve as guidance for further studies in order to discover molecular targets for the cancer therapy based on Aloe emodin treatment.

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“…Rac signaling is involved in the regulation of diverse tumor processes, such as tumorigenesis, survival, apoptosis and metastasis (Sun et al, 2006). Activation of Rac1 GTPase can induce EMT, and regulate the expression of MMPs (Mack et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

TIAM2 Enhances Non-small Cell Lung Cancer Cell Invasion and Motility

Zhao

Han²,

Liu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: TIAM2, a Rac guanine nucleotide exchange factor, is closely associated with cell adherence and migration. Here, we aimed to investigate the role of TIAM2 in non-small cell lung cancer (NSCLC) cells. Materials and Methods: A small interference RNA (siRNA) was introduced to silence the expression of TIAM2. Invasion and motility assays were then performed to assess the invasion and motility potential of NSCLC cells. GST-pull down assays were used to detect activation of Rac1. Results: TIAM2 was highly expressed in NSCLC cells. Knockdown of TIAM2 inhibited the invasion and motility, and suppressed activation of Rac1. Further experiments demonstrated that knockdown of TIAM2 could up-regulate the expression of E-cadherin, and downregulate the expression of MMP-3, Twist and Snail. Conclusions: Our data suggest that TIAM2 can promote invasion and motility of NSCLC cells. Activation of Rac1 and regulation of some EMT/invasion-related genes may be involved in the underlying processes.

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Rac signaling in tumorigenesis and as target for anticancer drug development

Cited by 50 publications

References 161 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

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

TIAM2 Enhances Non-small Cell Lung Cancer Cell Invasion and Motility

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