Vascular density is highest in the proximal region of the mouse prostate

Wang, Guimin; Kovalenko, Bruce; Wilson, E. Lynette; Moscatelli, David

doi:10.1002/pros.20582

Cited by 11 publications

(5 citation statements)

References 36 publications

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“…Negative controls were performed by replacing primary antibody with normal goat immunoglobulins. Then, the CD31-positive regions (in brown) were quantified using ImageJ 1.43, and vascularity density was calculated as the percent of tumor tissue area occupied by vessels as described (24).…”

Section: Methodsmentioning

confidence: 99%

Na/K-ATPase Mimetic pNaKtide Peptide Inhibits the Growth of Human Cancer Cells

Zhang²,

Xie³

et al. 2011

Journal of Biological Chemistry

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Cells contain a large pool of nonpumping Na/K-ATPase that participates in signal transduction. Here, we show that the expression of ␣1 Na/K-ATPase is significantly reduced in human prostate carcinoma as well as in several human cancer cell lines. This down-regulation impairs the ability of Na/KATPase to regulate Src-related signaling processes. A supplement of pNaKtide, a peptide derived from ␣1 Na/K-ATPase, reduces the activities of Src and Src effectors. Consequently, these treatments stimulate apoptosis and inhibit growth in cultures of human cancer cells. Moreover, administration of pNaKtide inhibits angiogenesis and growth of tumor xenograft. Thus, the new findings demonstrate the in vivo effectiveness of pNaKtide and suggest that the defect in Na/K-ATPase-mediated signal transduction may be targeted for developing new anticancer therapeutics. Na/K-ATPase was originally discovered as an ion pump that is essential for cell vitality and provides a means for epithelium to secrete and/or absorb solutes and nutrients (1, 2). Recent studies have revealed that in addition to pumping ions across the cell membrane, Na/K-ATPase, specifically the ␣1 isoform, conducts many nonpumping functions, including scaffolding and signal transduction. As a signaling protein, it is involved in the formation of membrane structures such as tight junction and caveolae (3, 4). Moreover, a large fraction of cellular Na/KATPase is involved in tethering and regulating multiple protein and lipid kinases as well as membrane receptors (e.g. Src, human epidermal growth factor receptor, and PI3K) in a cellspecific manner (5, 6). Recently, the ␣1 Na/K-ATPase-Src receptor complex has been identified as one of the central components of ␣1 Na/K-ATPase-mediated signaling transduction (7). In this receptor complex, the Src SH2 domain binds to the second cytosolic domain, whereas the Src kinase domain interacts with the nucleotide binding (N) domain 4 of the ␣1 subunit. The latter interaction keeps Src in an inactive state (7). It is important to note that normal epithelial cells express approximately one million ␣1 Na/K-ATPase molecules (roughly five times the amount of Src). Thus, ␣1 Na/K-ATPase could provide at least two ways of regulating cellular Src activity. First, it could bind and keep Src in an inactive state. Consistently, when knock-out of one copy of the ␣1 gene caused a 20 -30% reduction in cellular ␣1 Na/K-ATPase, it produced a Ͼ2-fold increase in Src and ERK activities in tissues of ␣1 ϩ/Ϫ mice (8). Second, formation of the Na/K-ATPase-Src complex provides a functional receptor for endogenous cardiotonic steroids such as ouabain to regulate cellular signaling via Src and Src effectors (7, 9). Thus, changes in cellular ␣1 Na/K-ATPase would have a significant effect on cellular signaling events induced by either cardiotonic steroids or other growth factors through Src-related pathways.Based on the fact that the N domain of the ␣1 subunit binds and inhibits Src, we have recently made pNaKtide from the N domain of the human ␣1 subunit of...

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Section: Methodsmentioning

confidence: 99%

Na/K-ATPase Mimetic pNaKtide Peptide Inhibits the Growth of Human Cancer Cells

Zhang²,

Xie³

et al. 2011

Journal of Biological Chemistry

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“…CD31 was used as an endothelial cell marker to facilitate the identification of CRFR2 in neovasculature of prostate cancer specimens accurately. CD31 serves as a reliable marker for angiogenesis and has been newly used for mapping of vascular density in different anatomical zones of prostate [22]. The tissue microarrays were stained for CRFR2 using goat polyclonal anti-human CRFR2 (Santa Cruz, CA) diluted 1:100 and prediluted mouse monoclonal anti-human CD31 (Abcam, Cambridge, UK) and the standard avidin-biotin system according to the manufacturer's protocols (Vector Laboratories, Burlingame, CA) with the exception that the peroxidase substrate diaminobenzidine was replaced by Atto 488 and Atto 655-labeled tyramides.…”

Section: Immunofluorescence and Confocal Microscopymentioning

confidence: 99%

The involvement of altered corticotropin releasing factor receptor 2 expression in prostate cancer due to alteration of anti‐angiogenic signaling pathways

et al. 2008

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BACKGROUND Expression of urocortin (Ucn) in the human benign prostate and prostate cancer has been reported recently. Ucn binds and activates corticotropin releasing factor (CRF) receptor 1 (CRFR1) and 2 (CRFR2). Activation of CRFR2 has been shown to inhibit tumor growth by regulation of proliferation and apoptosis as well as suppression of vascularization. However, there is no report demonstrating expression profile of CRFR2 in normal prostate versus prostate cancer. METHODS CRFR2 mRNA expression was assessed in human normal prostate and prostate cancer by reverse transcriptase PCR. CRFR2 expression on protein level has been performed using double staining immunofluorescence (IF) of tissue microarrays of 32 cases of prostatic adenocarcioma with corresponding normal tissues. Confocal microscopy was carried out to visualize the immunostaining. RESULTS PCR of normal prostate lysates exhibited specific signals for CRFR2 mRNA. However PCR of lysates of prostate cancer exhibited no signal for CRFR2 mRNA. IF study exhibited that smooth muscle components of the stroma and endothelial cells of blood vessels express an extensive staining for CRFR2. In a lesser extend vascular smooth muscle cells expressed CRFR2. The tumoral neovascular system and stroma exhibited no immunopositivity for CRFR2. CONCLUSIONS The present study demonstrates for the first time that human benign prostate tissue and prostate cancer specimen differentially express CRFR2. While Ucn expression in prostate cancer has been shown to be identical to non‐malignant prostate tissues, we hypothesize that expression loss of CRFR2 in prostate cancer and its neovascularization contributes to prostate tumorigenesis, progression, and neoangiogenesis. Prostate 69:443–448, 2009. © 2008 Wiley‐Liss, Inc.

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“…The growing vasculature would supply nutrients to support the expansion of the epithelial compartment. VEGF seems to play an essential role in the regulation of vascular growth in response to androgens as blocking VEGF signals with soluble VEGF receptors reduced vascular growth in the prostates of castrated mice administered testosterone (17,39) and inhibited regeneration of the prostate (16,17). However, in the experiment presented here, increased expression of VEGF did not alter the ability of endothelial cells to potentiate prostate tissue growth.…”

Section: Discussionmentioning

confidence: 53%