Examining the role of Rac1 in tumor angiogenesis and growth: a clinically relevant RNAi-mediated approach

Vader, Pieter; Meel, Roy van der; Symons, Marc; Fens, Marcel H.A.M.; Pieters, E.; Wilschut, Karlijn J.; Storm, Gert; Jarzabek, Monika A.; Gallagher, William M.; Schiffelers, Raymond M.; Byrne, Annette T.

doi:10.1007/s10456-011-9229-x

Cited by 37 publications

(39 citation statements)

References 37 publications

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“…Moreover, Rac1 inhibition on glioma stem-like cells enhanced radiation sensitivity 25. Rac1 has also been involved in angiogenesis in different tumoral settings, such as neuroblastoma26 and breast cancer 27. Inhibition of Rac1 using siRNA reduces vascular endothelial VEGF-mediated tubule formation, migration, and invasion in vitro, and these findings also are seen in vivo.…”

Section: Discussionmentioning

confidence: 99%

Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

Cardama¹,

González²,

Ciarlantini³

et al. 2014

OTT

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Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180–Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.

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Section: Discussionmentioning

confidence: 99%

Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

Cardama¹,

González²,

Ciarlantini³

et al. 2014

OTT

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“…Although Rac1 as a cytoskeleton organizer has been documented well, more and more recent findings provoked broad functions of Rac1 in human cancers. Rac1 regulates a diverse spectrum of cellular functions including tumorigenesis (11), angiogenesis (12,13) and metastasis (11,14,15). Overexpression of Rac1 occurs in several different types of tumors including breast (16,17), colon (18), bladder (19), and gastric cancer (20,21).…”

Section: Introductionmentioning

confidence: 99%

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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“…4D) and the increased VEGF levels (Fig. 4E) observed for miR-K6-5-transfected HUVECs might lead to increased angiogenesis of endothelial cells (31). To test this hypothesis, we transfected HUVECs with either miR-K6-5 or siBcr and quantified angiogenesis using a basement membrane matrix-based tube formation assay.…”

Section: Ementioning

confidence: 94%

“…Active Rac1 plays critical roles in regulating VEGF-induced endothelial cell motility, lumen formation, and, hence, angiogenesis (31,46,47). Transgenic mice expressing constitutively active Rac1 developed KS-like tumors (33).…”

Section: Ementioning

confidence: 99%

“…VEGF is a key proangiogenic factor and, upon binding to its receptors on the endothelial cell surface, stimulates angiogenesis by recruiting Rac1. Small interfering RNA (siRNA)-mediated knockdown of Rac1 reduces VEGF-induced angiogenesis in vitro and tumor progression in mice (31). Aberrant regulation of Rac1 has been observed for many cancers, including KS (32)(33)(34).…”

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confidence: 99%

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Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Repress Breakpoint Cluster Region Protein Expression, Enhance Rac1 Activity, and Increase In Vitro Angiogenesis

Ramalingam

Happel

Ziegelbauer

2015

J Virol

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Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a gammaherpesvirus that is associated with AIDS-associated KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1, 2). KSHV infects primarily cells of endothelial cell or B-cell origin and persists in either a latent phase, during which only a few viral genes are expressed, or a lytic phase, where the full repertoire of viral genes is expressed and infectious virions are released. During latent infection, KSHV also expresses 12 pre-microRNAs (premiRNAs) that are processed to yield ϳ20 mature miRNAs (3-6). miRNAs are ϳ22-nucleotide-long RNAs that typically bind with imperfect complementarity to the 3= untranslated regions (UTRs) of mRNAs and cause translational repression and mRNA degradation (7). The KSHV miRNAs are believed to be involved in repressing numerous targets that are involved in immune evasion (MICB) (8), apoptosis (BCLAF1, TWEAKR, and caspase 3) (9-11), lytic reactivation (RTA) (12, 13), angiogenesis (THBS1) (14), transcription repression (BACH1) (15,16), and cell signaling (p21, IB, and SMAD5) (17)(18)(19).Previously, we reported a microarray-based expression profiling approach to identify cellular mRNAs that are downregulated in the presence of KSHV miRNAs (11). From this array, we identified BCLAF1 (11), TWEAKR (9), and IRAK1 and MyD88 (20) as cellular targets of KSHV miRNAs. In this report, we identify the breakpoint cluster region (Bcr) mRNA and RacGAP1 as cellular targets of the KSHV miRNA miR-K12-6-5p (miR-K6-5).Bcr was originally identified as a fusion partner of Bcr-Abl, which is the fusion protein that is associated with most forms of chronic myelogenous leukemia (CML) and acute lymphocytic leukemias (ALLs) (21). Bcr by itself has been suggested to act as a tumor suppressor (22). Bcr interferes with the ␤-catenin-Tcf4

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Examining the role of Rac1 in tumor angiogenesis and growth: a clinically relevant RNAi-mediated approach

Cited by 37 publications

References 37 publications

Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells

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

Kaposi's Sarcoma-Associated Herpesvirus MicroRNAs Repress Breakpoint Cluster Region Protein Expression, Enhance Rac1 Activity, and Increase In Vitro Angiogenesis

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