Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis

Fernández-Zapico, Martín E.; González-Paz, Natalia; Weiss, Ellen A.; Savoy, Doris N.; Molina, Julian R.; Fonseca, Rafaël; Smyrk, Thomas C.; Chari, Suresh T.; Urrutia, Raúl; Billadeau, Daniel D.

doi:10.1016/j.ccr.2004.11.024

Cited by 197 publications

(238 citation statements)

References 36 publications

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“…In human lung cancer, multiple studies have revealed involvement of the deregulation of GEFs (18), such as Tiam1, ECT2, and Vav1-3 (19)(20)(21). In agreement, we demonstrated that ARHGEF5 was highly expressed in lung adenocarcinoma tissues and cultured cells.…”

Section: Discussionsupporting

confidence: 86%

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Yang

et al. 2015

Molecular Cancer Therapeutics

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We sought to elucidate the role of Rho guanine nucleotide exchange factor 5 (ARHGEF5) in tumorigenesis of lung adenocarcinoma cells. ARHGEF5 protein levels were assessed in 91 human lung adenocarcinoma specimens, and A549 and NCI-H1650 cells, by IHC and Western blotting. In addition, ARHGEF5 mRNA expression was evaluated by quantitative reverse transcriptase-PCR. Furthermore, ARHGEF5 long and short isoform coexpression was detected by immunofluorescence. Finally, flow cytometry; CCK8 and wound-healing assays; cell invasion, migration and adhesion; and xenografts were used to evaluate the biologic significance of ARHGEF5. ARHGEF5 was significantly increased in lung adenocarcinoma tissues and cell lines. Interestingly, ARHGEF5 levels were significantly associated with tumor grade and pathologic stage, but not age, gender, T stage, or lymph node metastasis status. ARHGEF5 knockdown by RNAi resulted in dramatically reduced proliferation, adhesion, invasion, and migratory capability of A549 and NCI-H1650 cells. Likewise, protein levels of p-Src, p-Akt, and NF-kB were significantly decreased after ARHGEF5 knockdown. In parallel, increased S-phase population and MMP-2/cyclin D1 expression were observed in the cancer cells, which were not apoptotic. In addition, ARHGEF5 knockdown A549 and NCI-H1650 cells injected s.c. and i.v. into nude mice exhibited decreased xenograft volume and overtly reduced metastasis. Conversely, ARH-GEF5 overexpression in A549 and NCI-H1650 cells increased their tumorigenicity in vitro. ARHGEF5 acts as a proto-oncogene in human lung adenocarcinoma cell tumorigenesis.

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Section: Discussionsupporting

confidence: 86%

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Yang

et al. 2015

Molecular Cancer Therapeutics

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“…EHT 1864 should be active against Rac activated by all RacGEFs. The importance of this property is emphasized by a recent study that found that Vav1 overexpression caused Racspecific and -dependent growth transformation of pancreatic carcinoma cells (60). Hence, EHT 1864, and not NSC23766, is expected to be an effective inhibitor of Vav1-driven pancreatic cancers, and our future studies will evaluate this possibility.…”

Section: Discussionmentioning

confidence: 92%

Specificity and Mechanism of Action of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

Shutes

Onesto

Picard

et al. 2007

Journal of Biological Chemistry

281

260

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There is now considerable experimental evidence that aberrant activation of Rho family small GTPases promotes the uncontrolled proliferation, invasion, and metastatic properties of human cancer cells. Therefore, there is considerable interest in the development of small molecule inhibitors of Rho GTPase function. However, to date, most efforts have focused on inhibitors that indirectly block Rho GTPase function, by targeting either enzymes involved in post-translational processing or downstream protein kinase effectors. We recently determined that the EHT 1864 small molecule can inhibit Rac function in vivo. In this study, we evaluated the biological and biochemical specificities and biochemical mechanism of action of EHT 1864. We determined that EHT 1864 specifically inhibited Rac1-dependent platelet-derived growth factor-induced lamellipodia formation. Furthermore, our biochemical analyses with recombinant Rac proteins found that EHT 1864 possesses high affinity binding to Rac1, as well as the related Rac1b, Rac2, and Rac3 isoforms, and this association promoted the loss of bound nucleotide, inhibiting both guanine nucleotide association and Tiam1 Rac guanine nucleotide exchange factor-stimulated exchange factor activity in vitro. EHT 1864 therefore places Rac in an inert and inactive state, preventing its engagement with downstream effectors. Finally, we evaluated the ability of EHT 1864 to block Rac-dependent growth transformation, and we determined that EHT 1864 potently blocked transformation caused by constitutively activated Rac1, as well as Rac-dependent transformation caused by Tiam1 or Ras. Taken together, our results suggest that EHT 1864 selectively inhibits Rac downstream signaling and transformation by a novel mechanism involving guanine nucleotide displacement.Rho family proteins (20 human members) comprise a major branch of the Ras superfamily of small GTPases (1, 2). Like Ras, Rho GTPases function as GDP/GTP-regulated binary on-off switches. In resting, quiescent cells, Rho GTPases exist predominately in their inactive, GDP-bound state. Upon growth factor stimulation, Rho-specific guanine nucleotide exchange factors (RhoGEFs) 4 are activated, and they stimulate the intrinsic guanine nucleotide exchange activity to promote formation of the active GTP-bound protein. Rho-GTP binds preferentially to downstream effector proteins. Rho-specific GTPaseactivating proteins then stimulate the intrinsic GTP hydrolysis activity of Rho GTPases, returning the protein to its inactive state and terminating effector interaction.RhoA, Rac1, and Cdc42 are the best studied and understood members of the Rho GTPase family (1, 2). Rho GTPases are regulators of a diverse variety of cellular processes that include regulation of cell proliferation, actin cytoskeleton reorganization, and gene expression (3). Like Ras and other members of the Ras superfamily (4, 5), the aberrant activity of Rho GTPases has been implicated in cancer and other human diseases (6 -10). In particular, the Rac subfamily has also been linked to c...

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“…Inhibition of NF-kB via super-repressor IkBa expression blocks angiogenesis and metastasis in human cancer-derived xenograft tumors (Fujioka et al, 2003). Mechanisms of NF-kB activation in pancreatic cancer appear to involve K-Ras and Akt activation, as well as Notch-1 signaling, nuclear glycogen synthase kinase-3b, and Vav1 (Wang et al, 1999c(Wang et al, , 2006Asano et al, 2004;Fernandez-Zapico et al, 2005;Ougolkov et al, 2005). Additionally, it has been reported that autocrine production of IL-1a regulates NF-kB activation in pancreatic cancer cells (Niu et al, 2004).…”

Section: Nf-kb and Pancreatic Cancermentioning

confidence: 99%

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

2006

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Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis

Cited by 197 publications

References 36 publications

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Rho Guanine Nucleotide Exchange Factor 5 Increases Lung Cancer Cell Tumorigenesis via MMP-2 and Cyclin D1 Upregulation

Specificity and Mechanism of Action of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

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