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Protein kinase C delta negatively modulates canonical Wnt pathway and cell proliferation in colon tumor cell lines.

ABSTRACT: The tumor suppressor Adenomatous Polyposis coli (APC) gene is mutated or lost in most colon cancers. Alterations in Protein kinase C (PKC) isozyme expression and aberrant regulation also comprise early events in intestinal carcinomas. Here we show that PKC? expression levels are decreased in colon tumor cell lines with respect to non-malignant cells. Reciprocal co-immunoprecipitation and immunofluorescence studies revealed that PKC? interacts specifically with both full-length (from non-malignant cells) and truncated APC protein (from cancerous cells) at the cytoplasm and at the cell nucleus. Selective inhibition of PKC? in cancer SW480 cells, which do not possess a functional ?-catenin destruction complex, did not affect ?-catenin-mediated transcriptional activity. However, in human colon carcinoma RKO cells, which have a normal ?-catenin destruction complex, negatively affected ?-catenin-mediated transcriptional activity, cell proliferation, and the expression of Wnt target genes C-MYC and CYCLIN D1. These negative effects were confirmed by siRNA-mediated knockdown of PKC? and by the expression of a dominant negative form of PKC? in RKO cells. Remarkably, the PKC? stably depleted cells exhibited augmented tumorigenic activity in grafted mice. We show that PKC? functions in a mechanism that involves regulation of ?-catenin degradation, because PKC? inhibition induces ?-catenin stabilization at the cytoplasm and its nuclear presence at the C-MYC enhancer even without Wnt3a stimulation. In addition, expression of a dominant form of PKC? diminished APC phosphorylation in intact cells, suggesting that PKC? may modulate canonical Wnt activation negatively through APC phosphorylation.

SUBMITTER: Hernandez-Maqueda JG

PROVIDER: S-EPMC3592802 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Protein kinase C delta negatively modulates canonical Wnt pathway and cell proliferation in colon tumor cell lines.

Hernández-Maqueda José G JG Luna-Ulloa Luis Bernardo LB Santoyo-Ramos Paula P Castañeda-Patlán M Cristina MC Robles-Flores Martha M

PloS one 20130308 3

The tumor suppressor Adenomatous Polyposis coli (APC) gene is mutated or lost in most colon cancers. Alterations in Protein kinase C (PKC) isozyme expression and aberrant regulation also comprise early events in intestinal carcinomas. Here we show that PKCδ expression levels are decreased in colon tumor cell lines with respect to non-malignant cells. Reciprocal co-immunoprecipitation and immunofluorescence studies revealed that PKCδ interacts specifically with both full-length (from non-malignan ...[more]

PMID: 23520519

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Project description:Colorectal cancer (CRC) is the third most diagnosed cancer in the western world, affecting 1 out of approximately 22 people in their lifetime. Several epidemiological studies suggest a positive association between high plasma cholesterol levels and colorectal cancer. However, the molecular mechanisms by which cholesterol may alter the risk of colorectal cancer (CRC) are ill-defined as the cholesterol lowering drugs statins do not appear to decrease a patient's risk of developing colorectal cancer. Cholesterol is metabolized to active derivatives including cholesterol oxidization products (COP), known as oxysterols, which have been shown to alter cellular proliferation. These metabolites and not cholesterol per se, may therefore affect the risk of developing colorectal cancer. The cholesterol metabolite or the oxysterol 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in the plasma and has been shown to be involved in the pathogenesis of several cancers including breast and prostate cancer. However, the role of 27-OHC in colorectal cancer has not been investigated. We treated Caco2 and SW620, two well characterized colon cancer cells with low, physiological and high concentrations of 27-OHC, and found that 27-OHC reduces cellular proliferation in these cells. We also found that the effects of 27-OHC on cell proliferation are not due to cellular cytotoxicity or apoptotic cellular death. Additionally, 27-OHC-induced reduction in cell proliferation is independent of actions on its target nuclear receptors, liver-X-receptors (LXR) and estrogen receptors (ER) activation. Instead, our study demonstrates that 27-OHC significantly decreases AKT activation, a major protein kinase involved in the pathogenesis of cancer as it regulates cell cycle progression, protein synthesis, and cellular survival. Our data shows that treatment with 27-OHC substantially decreases the activation of AKT by reducing levels of its active form, p-AKT, in Caco2 cells but not SW620?cells. All-together, our results show for the first time that the cholesterol metabolite 27-OHC reduces cell proliferation in colorectal cancer cells.

Dataset Information

Protein kinase C delta negatively modulates canonical Wnt pathway and cell proliferation in colon tumor cell lines.

Publications

Protein kinase C delta negatively modulates canonical Wnt pathway and cell proliferation in colon tumor cell lines.

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