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Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity

Oncogene volume 24, pages 1924–1935 (2005)Cite this article

Abstract

The FOXO family of Forkhead transcription factors, regulated by the phosphoinositide-3-kinase–Akt pathway, is involved in cell cycle regulation and apoptosis. Strong expression of HER2, a receptor tyrosine kinase oncogene, in cancers has been associated with a poor prognosis. Recently, FOXO4 was shown to regulate the transcription of the cyclin-dependent kinase inhibitor p27 Kip1 gene directly. Also, we have shown that HER2 promotes mitogenic growth and transformation of cancer cells by downregulation of p27 Kip1. Given the fact that FOXO4 mediates p27 transcription, we hypothesize that an Akt phosphorylation mutant of FOXO4 (FOXO4A3), which maintains the activity to transactivate p27 Kip1, may be used as an anticancer agent for HER2-overexpressing cancers. Here, we applied the FOXO4 gene as a novel anticancer agent for HER2-overexpressing cells under the control of a tetracycline (tet)-regulated gene expression system. Overexpression of FOXO4A3 inhibits HER2-activated cell growth. We found that FOXO4A3 inhibited the kinase activity of protein kinase B/Akt and reversed HER2-mediated p27 mislocation in the cytoplasm. FOXO4A3 expression also led to decreased levels of CSN5, a protein involved in p27 degradation. These data suggest that FOXO4A3 also can regulate p27 post-transcriptionally. In addition, we found that FOXO4A3 sensitized cells to apoptosis induced by the chemotherapeutic agent 2-methoxyestradiol. Most significantly for clinical application, FOXO4A3 expression in HER2-overexpressing cells can be regulated in vivo and reduces the tumor volume in a tumor model. These findings indicate the applicability of employing FOXO4 regulation as a therapeutic intervention in HER2-overexpressing cancers.

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Acknowledgements

We thank Drs Burgering, Pestell, and Qiu for valuable reagents, and Mayli Tsai and Ting-fang Che for technical help. This work was supported by a grant from the NIH RO1CA (089266) and by the Susan G Komen Breast Cancer Foundation. M-H Lee is a recipient of the Flemin and Davenport research award and the Susan G Koman Breast Cancer Foundation research award.

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  1. Huiling Yang

    Present address: Zhongshan Medical College, Sun Yat-Sen University, Guangzhou, People's Republic of China

Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Huiling Yang, Ruiying Zhao, Heng-Yin Yang & Mong-Hong Lee

  2. Programs in Genes & Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    Ruiying Zhao & Mong-Hong Lee

  3. Programs in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    Mong-Hong Lee

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Correspondence to Mong-Hong Lee.

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Yang, H., Zhao, R., Yang, HY. et al. Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene 24, 1924–1935 (2005). https://doi.org/10.1038/sj.onc.1208352

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