Original contributionIncreased expression of δ-catenin/neural plakophilin-related armadillo protein is associated with the down-regulation and redistribution of E-cadherin and p120ctn in human prostate cancer
Introduction
The complete mapping of the human genome has revealed many gene sequences that were not previously recognized as being associated with cancer. The rapid development of gene array technology has also helped the identification of genes that are up- or down-regulated in different types of cancers [1], [2]. These findings will help the establishment of molecular signatures of cancer [3], [4] and should facilitate more accurate diagnosis and treatment of cancer.
δ-Catenin, or neural plakophilin-related armadillo protein, is an adhesive junction–associated protein, initially identified as a neural-specific protein in the brain, and a binding partner to the presenilin 1 protein that has been prominently implicated in the progression of Alzheimer's disease [5], [6], [7], [8]. δ-Catenin belongs to the p120ctn subgroup in the armadillo/β-catenin superfamily of cell adhesion proteins [9], [10]. Initially designated as pp120 or p120CAS (cadherin-associated Src substrate), it was renamed to p120ctn to avoid confusion with a different Src substrate, p130CAS (Crk-associated substrate) [10]. In our previous studies, we found that δ-catenin interacts with classic cadherins, β-catenin, and p120ctn, and colocalizes with E-cadherin when ectopically expressed in Madin-Darby canine kidney (MDCK) epithelial cells [7]. δ-Catenin binds to the juxtamembrane domain (JMD) of classic cadherins, the same domain to which p120ctn also binds [11]. δ-Catenin expression leads to the redistribution of E-cadherin from basal-lateral domains toward apical sites in MDCK cells. δ-Catenin promotes cell scattering when epithelial cells are treated with hepatocyte growth factor [7], and it enhances the neurite outgrowth induced by the nerve growth factor in rat pheochromocytoma PC12 cells [12]. In developing hippocampal neurons, overexpression of δ-catenin promotes dendritic branching and spine-like protrusions [13], [14]. In NIH 3T3 fibroblast cells, ectopic expression of δ-catenin induces branched cytoplasmic extensions and the cytoskeletal reorganization [15]. These studies suggest that δ-catenin may operate downstream of growth factors and may be involved in signaling from growth factor receptors to the actin cytoskeleton to contribute to morphogenesis.
Although δ-catenin was subsequently found outside the central nervous system, the reports on the levels of δ-catenin expression in nonneuronal tissues have been varied. Initial immunochemical assays did not detect δ-catenin protein expression in tumor cell lines such as MCF-7 breast cancer cells, neuroepithelioma, and neuroblastoma cells [5]. However, recent complementary DNA (cDNA) micro-array comparisons of benign prostate hyperplasia and prostatic adenocarcinoma uncovered a significant enhancement of δ-catenin transcript in prostate cancer [16]. Examination of available human EST data bank also revealed δ-catenin messenger RNA (mRNA) sequences in kidney, ovarian, brain, breast, and esophageal tumors [17]. These observations are consistent with the finding that δ-catenin mRNA can be detected in cultures of SH-SY5Y human neuroblastoma cells, as well as the P19 human embryonal carcinoma stem cells of ependymal origin [7], [18]. Together, these findings suggest a possible δ-catenin association with cancer.
In this study, we used Western blots to investigate the expression of δ-catenin protein associated with prostate cancer. We performed immunohistochemistry on primary tumor tissue micro-array (TMA) consisting of 90 benign and 90 prostate cancer tissue samples to determine whether δ-catenin protein expression correlates with the down-regulation and redistribution of E-cadherin and p120ctn. Analyses of consecutive tissue sections allowed the determination of increased δ-catenin expression being compared directly with the changes in E-cadherin and p120ctn levels within the same tumor cell clusters. Combined with the transfection experiments, we have demonstrated, for the first time, that an increased expression of δ-catenin was not only correlated with E-cadherin and p120ctn down-regulation in primary adenocarcinomas, but the forced overexpression of δ-catenin in cultured CWR-R1 prostate cancer cells also induced the redistribution of E-cadherin and p120ctn, major cell-cell junction proteins whose inactivation is often linked to the aggressive phenotype of prostate cancer [19], [20].
Section snippets
Materials
Mouse anti–E-cadherin (Cat 20820), anti-pp120 (Cat 610133), and anti–δ-catenin D30 (Cat 611536) were from BD Biosciences (Palo Alto, Calif). Affinity-purified rabbit antihuman δ-catenin was developed as previously described [7], [21]. They were raised against amino acids 434 to 530 (rAB62), amino acids 828 to 1022 (rAb64), and amino acids 1213 to 1225 (rAb25). Mouse anti-actin was from Oncogene science (Boston, Mass). Unless otherwise indicated, all chemicals were from Sigma (St Louis, Mo).
Cell culture and cDNA transfection
PC12
δ-Catenin is overexpressed in prostate cancer cells
δ-Catenin is primarily expressed in the neurons of central nervous system and not present in the peripheral tissues such as bone marrow stroma [5], [6], [7]. To determine if δ-catenin protein expression is increased in prostate cancer cells, we first compared human marrow stromal cells HS-5 and noncancerous human prostate epithelial cells PZ-HPV-7 with CWR-R1, a cell line derived from a recurrent CWR22 human prostate tumor xenograft [27], [28]. Although Western blots showed that δ-catenin is
Discussion
δ-Catenin was initially identified as a presenilin binding protein [6], [8] and a neuronal adhesive junction–associated protein that is primarily expressed in the brain [5], [7]. Although its roles in presenilin-mediated Alzheimer's disease pathogenesis have not been established, recent studies demonstrated that δ-catenin is an important factor in neuronal morphogenesis [13], [14], [15].
In earlier studies, Northern blots showed that, besides the brain, only the pancreas displayed a weak signal
Acknowledgments
We deeply appreciate Werner Franke, Kenneth Kosik, and David Terrian for providing reagents; Beverly Jeansonne, Michele Laughinghouse, Larry Simonds, and Ginger Wescott for technical assistance; and members of the Lu lab for helpful suggestions and discussions.
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- 1
Supported in part by the American Cancer Society and The Brody School of Medicine Faculty Research Award.
- 2
Supported in part by the Department of Defense.
- 3
These authors contributed equally to the study.