Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

Guan, Ming; Tripathi, Veenu; Zhou, Xiaoling; Popescu, Nicholas C.

doi:10.1038/cgt.2008.13

Cited by 23 publications

(38 citation statements)

References 39 publications

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“…Treatment with trichostatin-A (TSA), a widely used HDAC inhibitor restored DLC1 expression in 22Rv1 cells and, to a lesser extent, in LNCap, but was ineffective in PC-3 cells (8). In contrast with other prostate carcinoma cells, Ad-DLC1-mediated transduction of PC-3 cells failed to induce apoptosis (9). These observations correlate strikingly with the sensitivity of prostate tumor cells to the induction of apoptosis by suberoylanilide hydroxamic acid (SAHA) (vorinostat), another potent HDAC inhibitor (10).…”

Section: Introductionmentioning

confidence: 99%

Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics

Zhou

Yang²,

Popescu³

2010

Int J Oncol

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Abstract. Inactivation of tumor suppressor genes is a major contributing alteration in the initiation or progression of cancer. The human tumor suppressor gene DLC1 (deleted in liver cancer 1) is frequently downregulated or silenced in multiple cancers, predominantly by epigenetic mechanisms. With the current considerable interest and progress in epigenetic therapy, a number of promising antineoplastic agents, particularly histone deacetylase (HDAC) inhibitors, have been developed and used successfully in clinical trials. Both DLC1 and HDAC inhibitors exert antineoplastic functions, and their combined action could be exploited for a more effective cancer therapy. To evaluate the potential benefits of this approach, we examined the antineoplastic effects of adenoviral (Ad)-DLC1-mediated transduction and exposure to suberoylanilide hydroxamic acid (SAHA), a powerful HDAC inhibitor, in two human cancer cell lines that lack intrinsic DLC1 expression, 22Rv1 prostate cancer cells and 7703K human hepatocellular carcinoma cells. Consistent with the oncosuppressive function of DLC1 in several cancers, including prostate and liver cancer, transduction of 22Rv1 and 7703K cells with an Ad-DLC1 expression vector resulted in alterations of cell morphology, induction of apoptosis, and inhibition of cell proliferation, migration, and anchorage-independent growth. A low concentration of SAHA (5 μM) efficiently restored the expression of DLC1 in 22Rv1 cells that lack DLC1 expression due to histone deacetylation but had a minimal effect in 7703K cells in which silencing of the DLC1 gene is due mainly to promoter hypermethylation. Regardless of the epigenetic mechanism of DLC1 inactivation, SAHA treatment of DLC1-transduced cells had a synergistic inhibitory effect on tumor cell proliferation and tumorigenesis in both cell lines. In 22Rv1 cells, this combination regimen nearly abolished the formation of colonies in semisolid media as a measure of tumorigenicity in vitro. Current in vitro results validate this protocol as a potentially new therapeutic option in certain cancers.

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Section: Introductionmentioning

confidence: 99%

Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics

Zhou

Yang²,

Popescu³

2010

Int J Oncol

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“…Adenovirus particles expressing the wild-type human DLC1 open reading frame (NM_006094) or LacZ were prepared as previously described (19) and used for transduction of cultured cells. For analysis of tumor formation in vivo, DLC1 was expressed using the plasmid vector pLXSN-DLC (20), which was prepared by cloning the DLC1 open reading frame into pLXSN (catalog no, 631509; Clontech Laboratories, Inc., Mountainview, CA, USA).…”

Section: Dlc1 Expression Vectorsmentioning

confidence: 99%

“…The MTT (Roche Diagnostics, Indianapolis, IN, USA) assay was used to test cell proliferation as previously described (19).…”

Section: -(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium Bromidementioning

confidence: 99%

Cooperative antiproliferative effect of coordinated ectopic expression of DLC1 tumor suppressor protein and silencing of MYC oncogene expression in liver cancer cells: Therapeutic implications

Yang¹,

Zhou²,

Tone

et al. 2016

Oncology Letters

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Abstract. Human hepatocellular carcinoma (HCC) is one of the most common types of cancer and has a very poor prognosis; thus, the development of effective therapies for the treatment of advanced HCC is of high clinical priority. In the present study, the anti-oncogenic effect of combined knockdown of c-Myc expression and ectopic restoration of deleted in liver cancer 1 (DLC1) expression was investigated in human liver cancer cells. Expression of c-Myc in human HCC cells was knocked down by stable transfection with a Myc-specific short hairpin (sh) RNA vector. DLC1 expression in Huh7 cells was restored by adenovirus transduction, and the effects of DLC1 expression and c-Myc knockdown on Ras homolog gene family, member A (RhoA) levels, cell proliferation, soft agar colony formation and cell invasion were measured. Downregulation of c-Myc or re-expression of DLC1 led to a marked reduction in RhoA levels, which was associated with decreases in cell proliferation, soft agar colony formation and invasiveness; this inhibitory effect was augmented with a combination of DLC1 transduction and c-Myc suppression. To determine whether liver cell-specific delivery of DLC1 was able to enhance the inhibitory effect of c-Myc knockdown on tumor growth in vivo, DLC1 vector DNA complexed with galactosylated polyethylene glycol-linear polyethyleneimine was administered by tail vein injection to mice bearing subcutaneous xenografts of Huh7 cells transfected with shMyc or control shRNA. A cooperative inhibitory effect of DLC1 expression and c-Myc knockdown on the growth of Huh7-derived tumors was observed, suggesting that targeted liver cell delivery of DLC1 and c-Myc shRNA may serve as a possible gene therapy modality for the treatment of human HCC. IntroductionHuman hepatocellular carcinoma (HCC) is one of the most common and lethal types of cancer, and its incidence is increasing worldwide (1,2). As numerous cases of HCC are diagnosed at later stages when the prognosis is poor, the development of effective therapy for advanced and metastatic HCC is a high clinical priority (1,2). HCC is a heterogeneous disorder with a complex pattern of genetic alterations, and increasing our knowledge of the specific genes and signaling pathways involved in the pathogenesis of HCC is critical for identifying novel clinical tools for diagnosis, classification and targeted therapy of the disease (3,4).Despite the heterogeneity of genomic alterations in HCC, certain chromosomes or chromosomal sites are more frequently deleted or amplified, resulting in deregulation of crucial genes that may ultimately trigger malignant transformation of healthy hepatocytes (5). Chromosome 8 exhibits a highly recurrent pattern of DNA copy number loss on the short arm (8p21-p22) and gain on the long arm (8q22-q24) (5,6), and these genetic alterations are associated with HCC subclasses with a less favorable outcome (7). The 8p and 8q sites correspond with the loci of the tumor suppressor gene deleted in liver cancer 1 (DLC1) and the c-Myc proto-oncogene, respectively (8...

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“…16,21,[23][24][25][26][27][28] Initially, the effects of DLC1 as a tumor suppressor were attributed to its RhoGAP activity, which has a significant role in cell growth, cytokinesis, morphogenesis, cell motility, trafficking, organization of cell cytoskeleton, transformation, and metastasis. 21,29 Subsequently, RhoGAPindependent tumor-suppressive mechanisms have also been identified. 21,30,31 Several binding partners of DLC1 have been identified, including members of the tensin family of focal adhesion proteins (eg, tensin1, tensin2, and C-terminal tensin like (cten)), p120RasGAP, elongation factor 1A1 (EF1A1), and S100A10, which further delineates its mechanism and its role in inhibiting cancer cell migration, proliferation, and metastasis.…”

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confidence: 99%

Loss of DLC1 is an independent prognostic factor in patients with oral squamous cell carcinoma

et al. 2012

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Deleted in liver cancer (DLC1), a Rho GTPase-activating protein, was observed to be differentially expressed in oral squamous cell carcinoma in comparison with normal tissues using tissue proteomics. In the current study, we investigated the clinical significance of loss of DLC1 expression in different stages of development of oral squamous cell carcinoma to determine its potential as a biomarker for oral dysplasia and prognosis of oral squamous cell carcinoma. Immunohistochemical analysis of DLC1 expression was carried out in oral squamous cell carcinoma patients (n ¼ 214), dysplasia (n ¼ 51), hyperplastic squamous mucosa (n ¼ 45), and histologically normal oral tissues (n ¼ 80), and correlated with clinicopathological parameters and disease prognosis over 91 months for oral squamous cell carcinomas. Loss of DLC1 expression was observed in oral squamous cell carcinoma (64%), oral dysplasia (31%), hyperplastic squamous mucosa (22%), and normal mucosa (16%). Significant loss of DLC1 expression was observed in oral squamous cell carcinomas as compared with dysplasia (Po0.001, odds ratio ¼ 3.8, 95% CI ¼ 2.0-7.3), suggesting it may be an important event involved in cancer progression. Among oral squamous cell carcinomas, the loss of DLC1 expression was significantly associated with poor prognosis (P ¼ 0.021, hazards ratio (HR) ¼ 1.8, 95% CI ¼ 1.1-2.9). Multivariate analysis revealed loss of DLC1 (P ¼ 0.023, HR ¼ 2.1, 95% CI ¼ 1.2-3.9) and histopathological grade (P ¼ 0.015, HR ¼ 1.7, 95% CI ¼ 1.1-2.7) to be independent predictors for disease-free survival in oral squamous cell carcinoma patients in comparison with known prognostic factors, viz. tumor stage, nodal status, and overall stage. Loss of DLC1 expression emerged as an important biomarker for predicting patients diagnosed with oral dysplasia at high risk of transformation upon future validation in longitudinal studies. Loss of DLC1 expression is a poor prognostic marker for oral squamous cell carcinoma patients.

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Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

Cited by 23 publications

References 39 publications

Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics

Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: Perspectives for therapeutics

Cooperative antiproliferative effect of coordinated ectopic expression of DLC1 tumor suppressor protein and silencing of MYC oncogene expression in liver cancer cells: Therapeutic implications

Loss of DLC1 is an independent prognostic factor in patients with oral squamous cell carcinoma

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