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?-Catenin promotes E-cadherin processing and activates ?-catenin-mediated signaling: implications on human prostate cancer progression.

ABSTRACT: ?-Catenin binds the juxtamembrane domain of E-cadherin and is known to be overexpressed in some human tumors. However, the functions of ?-catenin in epithelial cells and carcinomas remain elusive. We found that prostate cancer cells overexpressing ?-catenin show an increase in multi-layer growth in culture. In these cells, ?-catenin colocalizes with E-cadherin at the plasma membrane, and the E-cadherin processing is noticeably elevated. E-Cadherin processing induced by ?-catenin is serum-dependent and requires MMP- and PS-1/?-secretase-mediated activities. A deletion mutant of ?-catenin that deprives the ability of ?-catenin to bind E-cadherin or to recruit PS-1 to E-cadherin totally abolishes the ?-catenin-induced E-cadherin processing and the multi-layer growth of the cells. In addition, prostate cancer cells overexpressing ?-catenin display an elevated total ?-catenin level and increase its nuclear distribution, resulting in the activation of ?-catenin/LEF-1-mediated transcription and their downstream target genes as well as androgen receptor-mediated transcription. Indeed, human prostate tumor xenograft in nude mice, which is derived from cells overexpressing ?-catenin, shows increased ?-catenin nuclear localization and more rapid growth rates. Moreover, the metastatic xenograft tumor weights positively correlate with the level of 29kD E-cadherin fragment, and primary human prostate tumor tissues also show elevated levels of ?-catenin expression and the E-cadherin processing. Taken together, these results suggest that ?-catenin plays an important role in prostate cancer progression through inducing E-cadherin processing and thereby activating ?-catenin-mediated oncogenic signals.

SUBMITTER: Kim H

PROVIDER: S-EPMC3763829 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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δ-Catenin promotes E-cadherin processing and activates β-catenin-mediated signaling: implications on human prostate cancer progression.

Kim Hangun H He Yongfeng Y Yang Ilhwan I Zeng Yan Y Kim Yonghee Y Seo Young-Woo YW Murnane Mary Jo MJ Jung Chaeyong C Lee Jae-Hyuk JH Min Jeong-Joon JJ Kwon Dong-Deuk DD Kim Kyung Keun KK Lu Qun Q Kim Kwonseop K

Biochimica et biophysica acta 20120111 4

δ-Catenin binds the juxtamembrane domain of E-cadherin and is known to be overexpressed in some human tumors. However, the functions of δ-catenin in epithelial cells and carcinomas remain elusive. We found that prostate cancer cells overexpressing δ-catenin show an increase in multi-layer growth in culture. In these cells, δ-catenin colocalizes with E-cadherin at the plasma membrane, and the E-cadherin processing is noticeably elevated. E-Cadherin processing induced by δ-catenin is serum-depende ...[more]

PMID: 22261283

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Project description:Background: Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we provide initial evidence for potential roles of AKR1C3 in PCa progression. Methods: Spatial distribution of AKR1C3 was analyzed using immunohistochemical staining in prostate adenocarcinoma tissue array. Human PCa PC-3 cells were stably transfected with AKR1C3 cDNA to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analyses were performed to identify pathways that are activated by elevated AKR1C3 expression in PCa cells. Functional confirmation of microarray and bioinformatics results was performed by immunoblot analysis and an in vitro Matrigel angiogenesis assay. Results: Elevated AKR1C3 expression was specifically limited to human prostate adenocarcinoma. Microarray and bioinformatics analysis suggested that elevated AKR1C3 expression in PC-3 cells modulates estradiol and androgen metabolism and activates insulin growth factor (IGF)-1 and Akt signaling pathways. Immunoblots confirmed that phosphorylated levels of IGF-1 receptor (IGF-1R) and Akt are significantly up-regulated in PC3-AKR1C3 as compared to mock transfectants. PC3-AKR1C3 transfectants promoted endothelial cell tube formation in Matrigel as compared to parental PC-3 cells and mock transfectants. Conclusion: Microarray and bioinformatics data followed by biological analyses suggest that elevated AKR1C3 expression in PC-3 cells promotes PCa angiogenesis and aggressiveness. These results suggest AKR1C3 can promote the aggressiveness of PCa through modulating estrogen and androgen metabolism with subsequent activation of growth factor IGF-1 and cytoplasmic Akt signaling pathways. Total RNA from mock- and ACR1C3 transfected PC-3 cells was isolated, with 2 or 3 biological replicates each. Gene expression data from AKR1C3 transfected PC-3 cells were compared with mock-transfected data.

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Dataset Information

?-Catenin promotes E-cadherin processing and activates ?-catenin-mediated signaling: implications on human prostate cancer progression.

Publications

δ-Catenin promotes E-cadherin processing and activates β-catenin-mediated signaling: implications on human prostate cancer progression.

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