Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

RETRACTED ARTICLE: Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity

Oncogene volume 26, pages 7647–7655 (2007)Cite this article

This article was retracted on 19 October 2022

This article has been updated

Abstract

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 κB (NF-κB) and the activator protein 1 (AP-1) with a corresponding depletion in the expression of NF-κB 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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Change history

Abbreviations

AEG-1:

astrocyte-elevated gene-1

AP-1:

activator protein 1

FOXO:

forkhead box

IL-6:

Interleukin-6

IL-8:

Interleukin-8

MMP-9:

matrix metalloproteinase-9

NF-κB:

nuclear factor κB

PI3K:

phosphatidylinositol 3-kinase

PMO:

phosphorodiamidate morpholino antisense oligonucleotide

PTEN:

phosphatase and tensin homolog

References

  • Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB et al. (1997). Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7: 261–269.

    Article  CAS  Google Scholar 

  • Bader AG, Kang S, Zhao L, Vogt PK . (2005). Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 5: 921–929.

    Article  CAS  Google Scholar 

  • Bentires-Alj M, Hellin AC, Ameyar M, Chouaib S, Merville MP, Bours V . (1999). Stable inhibition of nuclear factor kappaB in cancer cells does not increase sensitivity to cytotoxic drugs. Cancer Res 59: 811–815.

    CAS  PubMed  Google Scholar 

  • Biggs III WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC . (1999). Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 96: 7421–7426.

    Article  CAS  Google Scholar 

  • Bradford MM . (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254.

    Article  CAS  Google Scholar 

  • Brown DM, Ruoslahti E . (2004). Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5: 365–374.

    Article  CAS  Google Scholar 

  • Chen X, Thakkar H, Tyan F, Gim S, Robinson H, Lee C et al. (2001). Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 20: 6073–6083.

    Article  CAS  Google Scholar 

  • Damen JE, Liu L, Rosten P, Humphries RK, Jefferson AB, Majerus PW et al. (1996). The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase. Proc Natl Acad Sci USA 93: 1689–1693.

    Article  CAS  Google Scholar 

  • Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K et al. (2006). Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 66: 1509–1516.

    Article  CAS  Google Scholar 

  • Festuccia C, Muzi P, Millimaggi D, Biordi L, Gravina GL, Speca S et al. (2005). Molecular aspects of gefitinib antiproliferative and pro-apoptotic effects in PTEN-positive and PTEN-negative prostate cancer cell lines. Endocr Relat Cancer 12: 983–998.

    Article  CAS  Google Scholar 

  • Ghosh S, Karin M . (2002). Missing pieces in the NF-κB puzzle. Cell 109: S81–S96.

    Article  CAS  Google Scholar 

  • Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB . (2005). Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene 353: 8–15.

    Article  CAS  Google Scholar 

  • Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB . (2006). Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA 103: 17390–17395.

    Article  CAS  Google Scholar 

  • Li P, Lee H, Guo S, Unterman TG, Jenster G, Bai W . (2003). AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR. Mol Cell Biol 23: 104–118.

    Article  Google Scholar 

  • Lu T, Burdelya LG, Swiatkowski SM, Boiko AD, Howe PH, Stark GR et al. (2004). Secreted transforming growth factor beta2 activates NF-kappaB, blocks apoptosis, and is essential for the survival of some tumor cells. Proc Natl Acad Sci USA 101: 7112–7117.

    Article  CAS  Google Scholar 

  • Lynch RL, Konicek BW, McNulty AM, Hanna KR, Lewis JE, Neubauer BL et al. (2005). The progression of LNCaP human prostate cancer cells to androgen independence involves decreased FOXO3a expression and reduced p27KIP1 promoter transactivation. Mol Cancer Res 3: 163–169.

    Article  CAS  Google Scholar 

  • Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K et al. (2006). Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 66: 7041–7049.

    Article  CAS  Google Scholar 

  • Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ et al. (1999). Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem 274: 21528–21532.

    Article  CAS  Google Scholar 

  • Nicholson KM, Anderson NG . (2002). The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14: 381–395.

    Article  CAS  Google Scholar 

  • Pajonk F, Pajonk K, McBride WH . (1999). Inhibition of NF-kappaB, clonogenicity, and radiosensitivity of human cancer cells. J Natl Cancer Inst 91: 1956–1960.

    Article  CAS  Google Scholar 

  • Place RF, Noonan EJ, Giardina C . (2005). HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha. Biochem Pharmacol 70: 394–406.

    Article  CAS  Google Scholar 

  • Plas DR, Thompson CB . (2003). Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem 278: 12361–12366.

    Article  CAS  Google Scholar 

  • Su ZZ, Chen Y, Kang DC, Chao W, Simm M, Volsky DJ et al. (2003). Customized rapid subtraction hybridization (RaSH) gene microarrays identify overlapping expression changes in human fetal astrocytes resulting from human immunodeficiency virus-1 infection or tumor necrosis factor-α treatment. Gene 306: 67–78.

    Article  CAS  Google Scholar 

  • Su ZZ, Kang DC, Chen Y, Pekarskaya O, Chao W, Volsky DJ et al. (2002). Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene 21: 3592–3602.

    Article  CAS  Google Scholar 

  • Takaishi H, Konishi H, Matsuzaki H, Ono Y, Shirai Y, Saito N et al. (1999). Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B. Proc Natl Acad Sci USA 96: 11836–11841.

    Article  CAS  Google Scholar 

  • Yang L, Xie S, Jamaluddin MS, Altuwaijri S, Ni J, Kim E et al. (2005). Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells. J Biol Chem 280: 33558–33565.

    Article  CAS  Google Scholar 

  • Zerbini LF, Wang Y, Cho JY, Libermann TA . (2003). Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. Cancer Res 63: 2206–2215.

    CAS  PubMed  Google Scholar 

  • Zhang M, Fang X, Liu H, Wang S, Yang D . (2007). Blockade of AKT activation in prostate cancer cells with a small molecule inhibitor, 9-chloro-2-methylellipticinium acetate (CMEP). Biochem Pharmacol 73: 15–24.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Roger Erickson for his support and assistance with the preparation of the manuscript. This study was supported by grants RO1CA101844, RO1AG021418, RO1CA108612, RO1CA111470 and T32DK07790 from the NIH, VA REAP award, Merit Review grants and Yamada Science Foundation.

Author information

Authors and Affiliations

  1. Department of Urology, Veterans Affairs Medical Center and University of California, San Francisco, CA, USA

    N Kikuno, K Kawamoto, H Hirata, Y Tanaka, R F Place, D Pookot, S Majid & R Dahiya

  2. Department of Urology, Shimane University School of Medicine, Izumo, Japan

    H Shiina, S Urakami & M Igawa

Authors
  1. N Kikuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Shiina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Urakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Kawamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R F Place
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Pookot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Majid
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Igawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R Dahiya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Dahiya.

About this article

Cite this article

Kikuno, N., Shiina, H., Urakami, S. et al. RETRACTED ARTICLE: Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 26, 7647–7655 (2007). https://doi.org/10.1038/sj.onc.1210572

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210572

Keywords

This article is cited by

Search

Advanced search

Quick links