Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity

• Published in: Oncogene Vol. 26; no. 55; pp. 7647 - 7655
• Main Authors: KIKUNO, N, SHIINA, H, DAHIYA, R, URAKAMI, S, KAWAMOTO, K, HIRATA, H, TANAKA, Y, PLACE, R. F, POOKOT, D, MAJID, S, IGAWA, M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 06-12-2007; Nature Publishing Group
• Subjects: Apoptosis; Apoptosis - genetics; Astrocytes; Biological and medical sciences; Care and treatment; Cell Adhesion Molecules - antagonists & inhibitors; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell culture; Cell Line, Tumor; Cell physiology; Cell Survival - drug effects; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Disease Progression; Down-Regulation; Forkhead Box Protein O3; Forkhead Transcription Factors - metabolism; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Genetics; Gynecology. Andrology. Obstetrics; Health aspects; Humans; Male; Male genital diseases; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular and cellular biology; Nephrology. Urinary tract diseases; NF-kappa B - metabolism; Oligonucleotides, Antisense - pharmacology; Oncology; Prevention; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-akt - metabolism; Transcription Factor AP-1 - metabolism; Tumors; Tumors of the urinary system; Up-Regulation; Urinary tract. Prostate gland; United States; Urinary system disease; Prostate disease; Neuroglia; Akt protein kinase; PTEN; AKT; Malignant tumor; Astrocyte; Carcinogenesis; AEG-1; Tumor progression; Inhibition; FOXO3a; Male genital diseases; Prostate cancer; Cancer; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210572

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.