SIRNA-Directed In Vivo Silencing of Androgen Receptor Inhibits the Growth of Castration-Resistant Prostate Carcinomas

Compagno, Daniel; Merle, Carole; Morin, Aurélie; Gilbert, Cristèle; Mathieu, Jacques; Bözec, Aline; Mauduit, Claire; Benahmed, Mohammed; Cabon, Florence

doi:10.1371/journal.pone.0001006

Cited by 55 publications

(70 citation statements)

References 44 publications

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“…The most pertinent question was whether TRPV2 silencing could inhibit tumor development in vivo. Previously, a RNA interference in vivo has been used to show that the androgen receptor is still required for the development of castration-resistant prostate tumors (25). Similarly, the model of mice bearing xenografted PC3 cell-provoked tumors has been created.…”

Section: Resultsmentioning

confidence: 99%

Role of Cationic Channel TRPV2 in Promoting Prostate Cancer Migration and Progression to Androgen Resistance

et al. 2010

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Castration resistance in prostate cancer (PCa) constitutes an advanced, aggressive disease with poor prognosis, associated with uncontrolled cell proliferation, resistance to apoptosis, and enhanced invasive potential. The molecular mechanisms involved in the transition of PCa to castration resistance are obscure. Here, we report that the nonselective cationic channel transient receptor potential vanilloid 2 (TRPV2) is a distinctive feature of castration-resistant PCa. TRPV2 transcript levels were higher in patients with metastatic cancer (stage M1) compared with primary solid tumors (stages T2a and T2b). Previous studies of the TRPV2 channel indicated that it is primarily involved in cancer cell migration and not in cell growth. Introducing TRPV2 into androgen-dependent LNCaP cells enhanced cell migration along with expression of invasion markers matrix metalloproteinase (MMP) 9 and cathepsin B. Consistent with the likelihood that TRPV2 may affect cancer cell aggressiveness by influencing basal intracellular calcium levels, small interfering RNA-mediated silencing of TRPV2 reduced the growth and invasive properties of PC3 prostate tumors established in nude mice xenografts, and diminished expression of invasive enzymes MMP2, MMP9, and cathepsin B. Our findings establish a role for TRPV2 in PCa progression to the aggressive castration-resistant stage, prompting evaluation of TRPV2 as a potential prognostic marker and therapeutic target in the setting of advanced PCa. Cancer Res; 70(3); 1225-35. ©2010 AACR.

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Section: Resultsmentioning

confidence: 99%

Role of Cationic Channel TRPV2 in Promoting Prostate Cancer Migration and Progression to Androgen Resistance

et al. 2010

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“…First, we determined whether the systemic delivery of siRNA by i.p. injection could reduce CEACAM6 expression and enhance viral replication in a subcutaneous Suit-2 xenograft tumor model (25). Delivery of CEACAM6-specific siRNA by i.p.…”

Section: A Suitable Cell Model For Screening Tumor-associated Genes Amentioning

confidence: 99%

“…Treatments with PBS, control siRNA, and CEACAM6 siRNA were administered on day 1, 2, and 3 by i.p. infection as described previously (25). For assessment of viral replication in vivo, 1 × 10 10 pt of replicating adenovirus vector expressing red fluorescent protein in 50 μl was injected intratumorally on day 4 after each injection of siRNAs and PBS.…”

Section: Evaluation Of Viral Replication and Antitumor Efficacy Of Admentioning

confidence: 99%

CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells

Wang¹,

Gangeswaran²,

Zhao³

et al. 2009

J. Clin. Invest.

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The changes in cancer cell surface molecules and intracellular signaling pathways during tumorigenesis make delivery of adenovirus-based cancer therapies inefficient. Here we have identified carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) as a cellular protein that restricts the ability of adenoviral vectors to infect cancer cells. We have demonstrated that CEACAM6 can antagonize the Src signaling pathway, downregulate cancer cell cytoskeleton proteins, and block adenovirus trafficking to the nucleus of human pancreatic cancer cells. Similar to CEACAM6 overexpression, treatment with a Src-selective inhibitor significantly reduced adenovirus replication in these cancer cells and normal human epithelial cells. In a mouse xenograft tumor model, siRNA-mediated knockdown of CEACAM6 also significantly enhanced the antitumor effect of an oncolytic adenovirus. We propose that CEACAM6-associated signaling pathways could be potential targets for the development of biomarkers to predict the response of patients to adenovirus-based therapies, as well as for the development of more potent adenovirus-based therapeutics.

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“…Androgen/AR signaling is required for androgensensitive LNCaP cells to proliferate. Yang et al [12] and Compagno et al [13] reported that the use of small interfering RNA (siRNA) to suppress endogenous AR in LNCaP cells led to apoptosis without proliferation. Similar results were also reported by Liao et al [14] and Haag et al [15].…”

Section: Lncap Cellsmentioning

confidence: 99%

The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

Yu¹,

Lai²,

Xia³

et al. 2008

Asian J Androl

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The androgen receptor (AR) plays an important role in the development and progression of prostate cancer (PCa). Androgen deprivation therapy is initially effective in blocking tumor growth, but it eventually leads to the hormonerefractory state. The detailed mechanisms of the conversion from androgen dependence to androgen independence remain unclear. Several PCa cell lines were established to study the role of AR in PCa, but the results were often inconsistent or contrasting in different cell lines, or in the same cell line grown under different conditions. The cellular and molecular alteration of epithelial cells and their microenvironments are complicated, and it is difficult to use a single cell line to address this important issue and also to study the pathophysiological effects of AR. In this paper, we summarize the different effects of AR on multiple cell lines and show the disadvantages of using a single human PCa cell line to study AR effects on PCa. We also discuss the advantages of widely used epithelium-stroma co-culture systems, xenograft mouse models, and genetically engineered PCa mouse models. The combination of in vitro cell line studies and in vivo mouse models might lead to more credible results and better strategies for the study of AR roles in PCa.

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SIRNA-Directed In Vivo Silencing of Androgen Receptor Inhibits the Growth of Castration-Resistant Prostate Carcinomas

Cited by 55 publications

References 44 publications

Role of Cationic Channel TRPV2 in Promoting Prostate Cancer Migration and Progression to Androgen Resistance

Role of Cationic Channel TRPV2 in Promoting Prostate Cancer Migration and Progression to Androgen Resistance

CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells

The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

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