Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity
| Autor: | N, Kikuno, H, Shiina, S, Urakami, K, Kawamoto, H, Hirata, Y, Tanaka, R F, Place, D, Pookot, S, Majid, M, Igawa, R, Dahiya |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Cell Survival Forkhead Box Protein O3 NF-kappa B Down-Regulation Membrane Proteins Prostatic Neoplasms RNA-Binding Proteins Apoptosis Forkhead Transcription Factors Oligonucleotides Antisense Up-Regulation Transcription Factor AP-1 Cell Line Tumor Disease Progression Humans Cell Adhesion Molecules Proto-Oncogene Proteins c-akt |
| Zdroj: | Oncogene. 26(55) |
| ISSN: | 1476-5594 |
| Popis: | Astrocyte-elevated gene-1 (AEG-1) has been reported to be upregulated in several malignancies and play a critical role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase/AKT signaling pathway. However, the role of AEG-1 in prostate cancer (PC) has never been reported. We now show that AEG-1 is overexpressed in clinical PC tissue samples and cultured PC cells compared to benign prostatic hyperplasia tissue samples and normal prostate epithelial cells. Interestingly, AEG-1 knockdown induced cell apoptosis through upregulation of forkhead box (FOXO) 3a activity. This alteration of FOXO3a activity was dependent on reduction of AKT activity in LNCaP and PC-3 cells with high constitutive AKT activity, but not in DU145 cells with low constitutive AKT activity, although AEG-1 knockdown had no impact on phosphatase and tensin homolog expression in these cells. AEG-1 knockdown also attenuated the constitutive activity of the nuclear factor kappaB (NF-kappaB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-kappaB and AP-1-regulated genes (interleukin (IL)-6, IL-8 and matrix metalloproteinase-9) and significantly decreased cell invasion properties of PC-3 and DU145 cells. Overall, our findings suggest that aberrant AEG-1 expression plays a dominant role as a positive auto-feedback activator of AKT and as a suppressor of FOXO3a in PC cells. AEG-1 may therefore represent a novel genetic biomarker to serve as an attractive molecular target for new anticancer agents to prevent PC cell progression and metastasis. |
| Databáze: | OpenAIRE |
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