Vav3-Rac1 Signaling Regulates Prostate Cancer Metastasis with Elevated Vav3 Expression Correlating with Prostate Cancer Progression and Posttreatment Recurrence

Lin, Kai-Ti; Gong, Jonathan; Li, Chien‐Feng; Jang, Te-Hsuan; Chen, Wenling; Chen, Huei-Jane; Wang, Lu‐Hai

doi:10.1158/0008-5472.can-11-2502

Cited by 60 publications

(52 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Vav3 is overexpressed in human prostate cancer samples versus benign tissue (5). Higher levels of Vav3 were recently demonstrated in metastatic human prostate cancer specimens, and Vav3 expression in primary disease was shown to predict earlier biochemical recurrence (9). Targeting a constitutively active Vav3 allele to prostate epithelium of transgenic mice results in prostate adenocarcinoma development (10).…”

Section: Elevated Androgen Receptor (Ar) Activity In Castration-mentioning

confidence: 99%

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

Wu¹,

Peacock

Rao³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The Rho GTPase guanine nucleotide exchange factor, Vav3, is overexpressed in human prostate cancer and enhances androgen receptor transcriptional activity. Results: Cdc37 is a novel Vav3 binding partner that enhances androgen receptor co-activation by Vav3 and increases prostate cancer cell proliferation. Conclusion: Vav3-Cdc37 interaction is required for maximal androgen receptor function and prostate cancer growth. Significance: Vav3-Cdc37 interaction is a potential therapeutic target for prostate cancer.

show abstract

Section: Elevated Androgen Receptor (Ar) Activity In Castration-mentioning

confidence: 99%

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

Wu¹,

Peacock

Rao³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…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 overexpression was observed in metastatic gastric (21), breast (15), prostate (22), bladder upper urinary tract cancer (19). Rac1 promoted prostate cancer progression and recurrence upon activation by VAV3, a GEF for Rac1 activation (14). Rac1 is also involved in sustained cell growth (23) and therapy resistance (24) through crosstalk with other signaling pathways.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Therefore, these molecules require direct validation to determine a potential direct relationship to GICs. We initially chose to primarily focus on VAV3 due its strong negative correlation with patient survival and frequent expression in cancers, including prostate cancer 32 and glioblastoma. 33,34 In five of eight glioma expression databases, elevated VAV3 expression informed statistically significant poor prognosis.…”

Section: Resultsmentioning

confidence: 99%

Phage display discovery of novel molecular targets in glioblastoma-initiating cells

et al. 2014

View full text Add to dashboard Cite

Glioblastoma is the most common primary intrinsic brain tumor and remains incurable despite maximal therapy. Glioblastomas display cellular hierarchies with self-renewing glioma-initiating cells (GICs) at the apex. To discover new GIC targets, we used in vivo delivery of phage display technology to screen for molecules selectively binding GICs that may be amenable for targeting. Phage display leverages large, diverse peptide libraries to identify interactions with molecules in their native conformation. We delivered a bacteriophage peptide library intravenously to a glioblastoma xenograft in vivo then derived GICs. Phage peptides bound to GICs were analyzed for their corresponding proteins and ranked based on prognostic value, identifying VAV3, a Rho guanine exchange factor involved tumor invasion, and CD97 (cluster of differentiation marker 97), an adhesion G-proteincoupled-receptor upstream of Rho, as potentially enriched in GICs. We confirmed that both VAV3 and CD97 were preferentially expressed by tumor cells expressing GIC markers. VAV3 expression correlated with increased activity of its downstream mediator, Rac1 (ras-related C3 botulinum toxin substrate 1), in GICs. Furthermore, targeting VAV3 by ribonucleic acid interference decreased GIC growth, migration, invasion and in vivo tumorigenesis. As CD97 is a cell surface protein, CD97 selection enriched for sphere formation, a surrogate of self-renewal. In silico analysis demonstrated VAV3 and CD97 are highly expressed in tumors and inform poor survival and tumor grade, and more common with epidermal growth factor receptor mutations. Finally, a VAV3 peptide sequence identified on phage display specifically internalized into GICs. These results show a novel screening method for identifying oncogenic pathways preferentially activated within the tumor hierarchy, offering a new strategy for developing glioblastoma therapies.

show abstract

Vav3-Rac1 Signaling Regulates Prostate Cancer Metastasis with Elevated Vav3 Expression Correlating with Prostate Cancer Progression and Posttreatment Recurrence

Cited by 60 publications

References 43 publications

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

Novel Interaction between the Co-chaperone Cdc37 and Rho GTPase Exchange Factor Vav3 Promotes Androgen Receptor Activity and Prostate Cancer Growth*

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

Phage display discovery of novel molecular targets in glioblastoma-initiating cells

Contact Info

Product

Resources

About