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Transgenic overexpression of PKC? in the mouse prostate induces preneoplastic lesions.

ABSTRACT: It is well established that protein kinase C (PKC) isozymes play distinctive roles in mitogenic and survival signaling as well as in cancer progression. PKC?, the product of the PRKCE gene, is up-regulated in various types of cancers including prostate, lung and breast cancer. To address a potential role for PKCs in prostate cancer progression we generated three mouse transgenic lines expressing PKC?, PKC?, or PKC? in the prostate epithelium under the control of the rat probasin (PB) promoter. Whereas PB-PKC? and PB-PKC? mice did not show any evident phenotype, PB-PKC? mice developed prostate hyperplasia as well as prostate intraepithelial neoplasia (PIN) that displayed enhanced phospho-Akt, phospho-S6, and phospho-Stat3 levels, as well as enhanced resistance to apoptotic stimuli. PKC? overexpression was insufficient to drive neoplastic changes in the mouse prostate. Notably, overexpression of PKC? by adenoviral means in normal immortalized RWPE-1 prostate cells confers a growth advantage and hyperactivation of Erk and Akt. Our results argue for a causal link between PKC? overexpression and prostate cancer development.

SUBMITTER: Benavides F

PROVIDER: S-EPMC3048798 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Transgenic overexpression of PKCε in the mouse prostate induces preneoplastic lesions.

Benavides Fernando F Blando Jorge J Perez Carlos J CJ Garg Rachana R Conti Claudio J CJ DiGiovanni John J Kazanietz Marcelo G MG

Cell cycle (Georgetown, Tex.) 20110115 2

It is well established that protein kinase C (PKC) isozymes play distinctive roles in mitogenic and survival signaling as well as in cancer progression. PKCε, the product of the PRKCE gene, is up-regulated in various types of cancers including prostate, lung and breast cancer. To address a potential role for PKCs in prostate cancer progression we generated three mouse transgenic lines expressing PKCα, PKCδ, or PKCε in the prostate epithelium under the control of the rat probasin (PB) promoter. W ...[more]

PMID: 21224724

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Project description:Colorectal cancer (CRC) is one of the leading causes of cancer morbidity and mortality in Western countries. One of the risk factors for colorectal tumorigenesis is vitamin D insufficiency. The aim of this study was to establish whether increasing dietary vitamin D intake can prevent or delay development of chemically induced preneoplastic lesions in the colon of mice. We fed six weeks old female C57BL/6J mice (n=28) with increasing vitamin D3 concentrations (100, 400, 1000, 2500, 5000IU/kg diet). To induce dysplasia, a preneoplastic lesion, we injected mice with the carcinogen azoxymethane (10mg/kg) intraperitoneally, followed by three cycles of 2% dextran sodium sulfate salt, a tumor promoter, in the drinking water. To test our hypothesis that high vitamin D intake prevents formation of preneoplastic lesions, we have investigated the effect of increasing dietary vitamin D on development of premalignant colorectal lesions, serum 25-hydroxyvitamin D3 (25-D3) levels, and expression of renal vitamin D system genes. Dietary vitamin D concentration correlated inversely with dysplasia score (Spearman's correlation coefficient, ?: -0.579, p=0.002) and positively with serum 25-D3 levels (?: 0.752, p=0.001). Increasing dietary vitamin D concentration beyond 1000IU/kg led to no further increase in circulating 25-D3 levels, while the dysplasia score leveled out at ?2500IU/kg vitamin D. High dietary vitamin D intake led to increased renal mRNA expression of the vitamin D catabolizing enzyme cyp24a1 (?: 0.518, p=0.005) and decreased expression of the vitamin D activating enzyme cyp27b1 (?: -0.452, p=0.016), protecting the body from toxic serum levels of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25-D3). Our data showed that increasing dietary vitamin D intake is able to prevent chemically induced preneoplastic lesions. The maximum impact was achieved when the mice consumed more than 2500IU vitamin D/kg diet. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Dataset Information

Transgenic overexpression of PKC? in the mouse prostate induces preneoplastic lesions.

Publications

Transgenic overexpression of PKCε in the mouse prostate induces preneoplastic lesions.

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