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Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis

Oncogene volume 33, pages 3660–3667 (2014)Cite this article

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Abstract

Mutations in the PTEN tumor suppressor gene are found in a high proportion of human prostate cancers, and in mice, Pten deletion induces high-grade prostate intraepithelial neoplasia (HGPIN). However, progression from HGPIN to invasive cancer occurs slowly, suggesting that tumorigenesis is subject to restraint. We show that Pten deletion, or constitutive activation of the downstream kinase AKT, activates the transforming growth factor (TGF)β pathway in prostate epithelial cells. TGFβ signaling is known to have a tumor suppressive role in many cancer types, and reduced expression of TGFβ receptors correlates with advanced human prostate cancer. We demonstrate that in combination either with loss of Pten or expression of constitutively active AKT1, inactivation of TGFβ signaling by deletion of the TGFβ type II receptor gene relieves a restraint on tumorigenesis. This results in rapid progession to lethal prostate cancer, including metastasis to lymph node and lung. In prostate epithelium, inactivation of TGFβ signaling alone is insufficient to initiate tumorigenesis, but greatly accelerates cancer progression. The activation of TGFβ signaling by Pten loss or AKT activation suggests that the same signaling events that have key roles in tumor initiation also induce the activity of a pathway that restrains disease progression.

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Acknowledgements

We thank Sharon Birdsall and Marya Brown for technical assistance, Doug DeSimone for use of the Zeiss microscope, Anindya Dutta and Dan Gioeli for helpful discussions and Tiffany Melhuish for expert advice and assistance. This work was supported by a Program Project Grant from the National Cancer Institute (2P01CA104106 to B Paschal and D Wotton), and by a pilot grant from the UVA Cancer Center (funded from the CCSG P30 CA44579, the James and Rebecca Craig Foundation, and UVA Women’s Oncology fund) to D Wotton.

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  1. Department of Biochemistry and Molecular Genetics, and Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA

    G A Bjerke, C-S Yang, B M Paschal & D Wotton

  2. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    H F Frierson

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  1. G A Bjerke
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  2. C-S Yang
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Correspondence to D Wotton.

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Bjerke, G., Yang, CS., Frierson, H. et al. Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. Oncogene 33, 3660–3667 (2014). https://doi.org/10.1038/onc.2013.342

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