Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells

Baugher, Paige J.; Krishnamoorthy, Lakshmi; Price, Janet E.; Dharmawardhane, Surangani

doi:10.1186/bcr1329

Cited by 111 publications

(112 citation statements)

References 33 publications

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“…1, A and B). Several laboratories have shown that MDA-MB-435 cells exhibit significant levels of Rac activity (44,45). We confirmed this result and observed a slight decrease in Rac activity upon arachidonic acid treatment (supplemental Fig.…”

Section: Resultssupporting

confidence: 79%

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Garcia

Ray

Lackford

et al. 2009

Journal of Biological Chemistry

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Rho GTPases are critical components of cellular signal transduction pathways. Both hyperactivity and overexpression of these proteins have been observed in human cancers and have been implicated as important factors in metastasis. We previously showed that dietary n-6 fatty acids increase cancer cell adhesion to extracellular matrix proteins, such as type IV collagen. Here we report that in MDA-MB-435 human melanoma cells, arachidonic acid activates RhoA, and inhibition of RhoA signaling with either C3 exoenzyme or dominant negative Rho blocked arachidonic acid-induced cell adhesion. Inhibition of the Rho kinase (ROCK) with either small molecule inhibitors or ROCK II-specific small interfering RNA (siRNA) blocked the fatty acid-induced adhesion. However, unlike other systems, inhibition of ROCK did not block the activation of p38 mitogenactivated protein kinase (MAPK); instead, Rho activation depended on p38 MAPK activity and the presence of heat shock protein 27 (HSP27), which is phosphorylated downstream of p38 after arachidonic acid treatment. HSP27 associated with p115RhoGEF in fatty acid-treated cells, and this association was blocked when p38 was inhibited. Furthermore, siRNA knockdown of HSP27 blocked the fatty acid-stimulated Rho activity. Expression of dominant negative p115-RhoGEF or p115RhoGEF-specific siRNA inhibited both RhoA activation and adhesion on type IV collagen, whereas a constitutively active p115RhoGEF restored the arachidonic acid stimulation in cells in which the p38 MAPK had been inhibited. These data suggest that n-6 dietary fatty acids stimulate a set of interactions that regulates cell adhesion through RhoA and ROCK II via a p38 MAPK-dependent association of HSP27 and p115RhoGEF.The ability of tumor cells to metastasize to secondary sites is a hallmark of neoplastic disease. Unfortunately, this propensity to spread is the primary cause of morbidity and death in cancer patients (1). Metastasis is clearly a highly regulated, multistep process that occurs in a spatiotemporal manner (2-4). To escape the restrictive compartment boundaries characteristic of adult tissue, separate intravasation and extravasation steps requiring alterations in co-adhesion, adhesion, invasion, and migration must occur. Execution of these biological processes, involving multiple proteins and cellular organelles, require highly coordinated cell signaling mechanisms.The Rho family of small GTPases regulates many facets of cytoskeletal rearrangements that facilitate cell attachment and migration (5-7). Rho GTPases act as molecular switches by changing from an inactive GDP-bound conformation to an active GTPbound conformation, thereby regulating a signaling pathway. These proteins are directly regulated by Rho guanine nucleotide exchange factors (GEFs), 2 Rho GTPase activating proteins, and Rho GDP-dissociation inhibitors (8 -12). RhoGEFs bind to the GTPase to catalyze the dissociation of GDP, allowing the binding of GTP and thereby promoting Rho activation (8). The RGS (regulators of G protein signaling) domain-c...

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Section: Resultssupporting

confidence: 79%

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Garcia

Ray

Lackford

et al. 2009

Journal of Biological Chemistry

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“…Rac1 promoted colon cancer progression through promotion of cell proliferation, survival and migration (36). Rac1 expression is correlated with tumorigenesis, aggressiveness and treatment resistance in a number of cancers such as lung (37,38), breast cancer (39,40) and melanoma (23,41). These clinical investigations have shown the close correlation of Rac1 with human cancers.…”

Section: Discussionmentioning

confidence: 93%

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Feng

Shi

et al. 2015

International Journal of Oncology

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Abstract. Rac1 is a member of the Rho GTPase family. Rac1 activity is critical in regulating cytoskeleton organization and thus, modulates a diverse spectrum of cellular functions in normal and malignant cells. The aims of the present study were to investigate the expression pattern and clinical significance of Rac1, as well as the role of Rac1 in gastric cancer tumorigenesis and metastasis. The expression of Rac1 in human gastric cancer was explored by immunohistochemistry. The correlation of Rac1 expression with the clinicopathological characteristics and the survival of patients were analyzed by Pearson's Chi-square and KaplanMeier analyses, respectively. Rac1 overexpression cell model was used to examine in vitro and in vivo effects of Rac1 in cell growth, migration and invasion. Rac1 was highly expressed in gastric cancer tissues and correlated with differentiation, local invasion, lymph node metastasis and Lauren's classification. Rac1 expression in gastric cancer predicted shorter survival. Overexpression of Rac1 in gastric cancer cells dramatically induced Rac1 activation and rendered a more aggressive phenotype such as increased cell growth and migration/invasion in vitro and in vivo. Inhibiting Rac1 activity by specific inhibitor abrogated the effects of Rac1 on the malignant phenotype. Our clinical findings demonstrated that Rac1 was well correlated with aggressiveness and a negative prognostic factor. In addition, our data on experimental cell models supported the fundamental role of Rac1 in gastric cancer. Given its pivotal role in gastric tumorigenesis and progression, Rac1 can serve as a promising therapeutic target for gastric cancer.

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“…The aberrant Rac1 activity has been correlated with several aspects of malignancy in human breast cancers (17,27,(44)(45)(46)(47)(48). We sought to determine whether blockade of Rac1 activity could be beneficial in suppressing breast cancer cell growth and survival.…”

Section: Resultsmentioning

confidence: 99%

“…The dysregulated Rac1 activity has been implicated in several aspects of malignant phenotypes such as tumorigenic transformation and outgrowth (21)(22)(23)(24)(25). Rac1 is also integral in the regulation of tumor angiogenesis through its control over epithelial cell motility (26)(27)(28) and endothelial cell permeability (29,30). We (6)(7)(8) and others (31)(32)(33)(34) have shown that Rac1 activity contributes to the resistance of cancer cells to apoptosis by different chemotherapies.…”

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 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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Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells

Cited by 111 publications

References 33 publications

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

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

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