Rho GTPase-Activating Protein Deleted in Liver Cancer Suppresses Cell Proliferation and Invasion in Hepatocellular Carcinoma

Wong, Kwong-Kwok; Chang, Yi Mieng; Tsang, Yvonne T.M.; Perlaky, László; Su, Johnny; Adesina, Adekunle M.; Armstrong, Dawna L.; Bhattacharjee, Meenakshi B.; Dauser, Robert C.; Blaney, Susan M.; Chintagumpala, Murali; Ching, Yick–Pang

doi:10.1158/0008-5472.can-05-1318

Cited by 174 publications

(213 citation statements)

References 38 publications

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“…For instance, DLC1 (deleted in liver cancer), a GAP for Rho proteins, suppresses cell proliferation, migration and invasion in hepatocellular carcinoma cells. DLC1 is thought to serve as a tumor suppressor protein by antagonizing the oncogenic activity of Rho proteins in liver cancer (Wong et al, 2005;Xue et al, 2008). In contrast, p190A RhoGAP-deficient fibroblasts showed a defect in polarized cell migration (Tomar et al, 2009) although they did not exhibit any obvious defects in adhesion on extracellular matrix (Jiang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Northey

Primeau

et al. 2010

Oncogene

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RhoA, Rac1 and Cdc42, the best-characterized members of the Rho family of small GTPases, are critical regulators of many cellular activities. Cdc42 GTPaseactivating protein (CdGAP) is a serine-and proline-rich RhoGAP protein showing GAP activity against both Cdc42 and Rac1 but not RhoA. CdGAP is phosphorylated downstream of the MEK-ERK (extracellular signalregulated kinase) pathway in response to serum and is required for normal cell spreading and polarized lamellipodia formation. In this study, we found that CdGAP protein and mRNA levels are highly increased in mammary tumor explants expressing an activated Neu/ ErbB-2 (Neu-NT) receptor. In response to transforming growth factor-b (TGFb) stimulation, Neu-NT-expressing mammary tumor explants demonstrate a clear induction in cell motility and invasion. We show that downregulation of CdGAP expression by small interfering RNA abrogates the ability of TGFb to induce cell motility and invasion of Neu-NT-expressing mammary tumor explants. However, it has no effect on TGFb-mediated cell adhesion on type 1 collagen and fibronectin. Interestingly, protein expression of E-Cadherin is highly increased in Neu-NT-expressing mammary tumor explants depleted of CdGAP. In addition, complete loss of E-Cadherin expression is not observed in CdGAP-depleted cells during TGFb-mediated epithelial to mesenchymal transition. Downregulation of the CdGAP expression also decreases cell proliferation of Neu-NT-expressing mammary tumor explants independently of TGFb. Rescue analysis using re-expression of various CdGAP deletion-mutant proteins revealed that the proline-rich domain (PRD) but not the GAP domain of CdGAP is essential to mediate TGFbinduced cell motility and invasion. Finally, we found that TGFb induces the expression and phosphorylation of CdGAP in mammary epithelial NMuMG cells. Taken together, these studies identify CdGAP as a novel molecular target in TGFb signaling and implicate CdGAP as an essential component in the synergistic interaction between TGFb and Neu/ErbB-2 signaling pathways in breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Northey

Primeau

et al. 2010

Oncogene

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“…Indeed, DLC1 is emerging as a bona fide tumor suppressor gene, given that ectopic expression of DLC-1 in several common types human cancer cells that do not express the endogenous gene inhibits cell proliferation and induces caspase-3-mediated apoptosis in vitro as well as abolishes or reduces tumorigenicity in vivo [2,3,4,5,6,7,8]. Limited information is available on factors that regulate transcription of endogenous DLC1, however.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

Ullmannova

Popescu

2007

Cancer Detection and Prevention

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Background-Dietary flavone was previously shown to increase the expression of deleted in liver cancer-1 gene (DLC-1) in HT-29 colon carcinoma cell line (Proteomics 2004;4:2455-64). DLC-1 that encodes a Rho GTPase-activating protein, functions as a tumor suppressor gene and is frequently inactivated or down-regulated in several common cancers. Restoration of DLC-1 expression suppresses in vitro tumor cells proliferation and tumorigenicity in vivo.Methods-Here, the effect of flavone was examined in several DLC-1-deficient cell lines derived from different types human cancer using assays for cell proliferation, gene expression and transfer.Results-We show that exposure to 15μM flavone increased DLC1 expression in breast but not in liver or prostate carcinoma cells or a nonmalignant breast epithelial cell line. Flavone restored the expression of DLC1 in the breast carcinoma cell lines MDA-MB-468, MDA-MB-361, and BT20 as well as in the colon carcinoma cell line HT-29 all of which are DLC-1-negative due to promoter hypermethylation. We further show that flavone inhibited cell proliferation, induced cell cycle arrest at G2-M, increased p21 Waf1 gene expression, and caused apoptosis. Microarray analysis of these aggressive and metastatic breast carcinoma cells revealed 29 flavone-responsive genes, among which the DNA damage-inducible GADD genes were up-regulated and the proto-oncogene STMN1 and IGFBP3 were down-regulated.Conclusions-Flavone-mediated alterations of genes that regulate tumor cell proliferation, cell cycle, and apoptosis contribute to chemopreventive and antitumoral effects of flavone. Alone or in combination with demethylating agents, flavone may be an effective adjunct to chemotherapy in preventing breast cancer metastasis.

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“…However, the activation of Rho proteins contributes to tumorigenesis and metastasis in many cancers 10 , and RhoGAP activity has a predominant role in the tumour suppressor functions of DLC1 11 . In different cell line models, ectopic expression of the RhoGAP mutant of DLC1 fails to suppress cell growth and motility 12,13 , and functional studies have shown that RhoGAP and the growth inhibitory activities of DLC1 are impaired as a result of T301K and S308I mutations, which were identified in prostate and colon cancer patients 14 . These studies suggest that RhoGAP activity and growth suppression activity are tightly associated.…”

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confidence: 99%

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Chan

Sze

et al. 2013

Nat Commun

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Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that encodes a RhoGTPase-activating protein (RhoGAP) and is frequently inactivated in many human cancers. The RhoGAP activity of DLC1 against Rho signalling is well documented and is strongly associated with the tumour suppressor functions of DLC1. However, the mechanism by which the RhoGAP activity of DLC1 is regulated remains obscure. Here, we report that phosphorylation of DLC1 at Ser549 by cyclic AMP-dependent protein kinase A contributes to enhanced RhoGAP activity and promotes the activation of DLC1, which suppresses hepatoma cell growth, motility and metastasis in both in vitro and in vivo models. Intriguingly, we found that Ser549 phosphorylation induces the dimerization of DLC1 and that inducible dimerization of DLC1 can rescue the tumour suppressive and RhoGAP activities of DLC1 containing a Ser549 deletion. Our study establishes a novel regulatory mechanism for DLC1 RhoGAP activity via dimerization induced by protein kinase A signalling.

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Rho GTPase-Activating Protein Deleted in Liver Cancer Suppresses Cell Proliferation and Invasion in Hepatocellular Carcinoma

Cited by 174 publications

References 38 publications

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

CdGAP is required for transforming growth factor β- and Neu/ErbB-2-induced breast cancer cell motility and invasion

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

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