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FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells

Oncogene volume 27, pages 4422–4433 (2008)Cite this article

Abstract

Androgen-withdrawal-induced apoptosis (AWIA) is deregulated in androgen refractory prostate cancer. Androgens have been shown to positively regulate expression of the antiapoptotic FADD-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein (FLIP), and reduced FLIP expression precedes apoptosis after androgen withdrawal. Here, we show that FLIP protein expression is downregulated in castrated rats, while in LNCaP cells, androgens regulate FLIP in a manner that is dependent on phosphoinositol-3-kinase (PI3K) and Akt signaling. Specifically, treatment of LNCaP cells with LY294002, or expression of either PTEN or a non-phosphorylatable form of FOXO3a (FOXO3aTM), downregulates FLIP protein and mRNA. Conversely, treatment with androgens in the absence of PI3/Akt signaling, or following expression of FOXO3aTM, leads to increased FLIP expression. A FOXO3a binding site was identified in the FLIP promoter and shown necessary for the combined effects of androgens and FOXO3a on FLIP transcription. FOXO3a binds the androgen receptor, suggesting that the transcriptional synergy depends on an interaction between these proteins. Finally, LNCaP cells are sensitized to TRAIL-induced apoptosis by PTEN or LY294002, and rescued by androgens. FOXO3aTM also sensitizes cells to androgen-inhibited TRAIL apoptosis. Androgen rescue was diminished when either FOXO3a or FLIP was reduced by siRNA. These data support a role for FOXO3a in AWIA.

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Acknowledgements

This study was supported by grant PC030937 from the US Army Prostate Cancer Research Program. ANC was supported by a PHS training grant (5T32CA009054). We thank D Fruman, R Miesfeld, K Guan and M Greenberg for plasmids, and C Walsh and D Fruman for assistance with FACS analysis.

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  1. Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA

    A N Cornforth, J S Davis, E Khanifar, K L Nastiuk & J J Krolewski

  2. Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, CA, USA

    J J Krolewski

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  1. A N Cornforth
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  2. J S Davis
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  3. E Khanifar
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Correspondence to J J Krolewski.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Cornforth, A., Davis, J., Khanifar, E. et al. FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells. Oncogene 27, 4422–4433 (2008). https://doi.org/10.1038/onc.2008.80

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