Article | Published:

Translational Therapeutics

Endothelial Akt1 loss promotes prostate cancer metastasis via β-catenin-regulated tight-junction protein turnover

British Journal of Cancervolume 118pages14641475 (2018) | Download Citation

Abstract

Background

Cancer research, in general, is focused on targeting tumour cells to limit tumour growth. These studies, however, do not account for the specific effects of chemotherapy on tumour endothelium, in turn, affecting metastasis.

Methods

We determined how endothelial deletion of Akt1 promotes prostate cancer cell invasion in vitro and metastasis to the lungs in vivo in endothelial-specific Akt1 knockdown mice.

Results

Here we show that metastatic human PC3 and DU145 prostate cancer cells invade through Akt1-deficient human lung endothelial cell (HLEC) monolayer with higher efficiency compared to control HLEC. Although the endothelial Akt1 loss in mice had no significant effect on RM1 tumour xenograft growth in vivo, it promoted metastasis to the lungs compared to the wild-type mice. Mechanistically, Akt1-deficient endothelial cells exhibited increased phosphorylation and nuclear translocation of phosphorylated β-catenin, and reduced expression of tight-junction proteins claudin-5, ZO-1 and ZO-2. Pharmacological inhibition of β-catenin nuclear translocation using compounds ICG001 and IWR-1 restored HLEC tight-junction integrity and inhibited prostate cancer cell transendothelial migration in vitro and lung metastasis in vivo.

Conclusions

Here we show for the first time that endothelial-specific loss of Akt1 promotes cancer metastasis in vivo involving β-catenin pathway.

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Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

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Acknowledgements

This work has been accomplished using the resources and facilities at Charlie Norwood Medical Center in Augusta, GA.

Author information

Affiliations

  1. Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA, 30912, USA

    • Fei Gao
    • , Abdulrahman Alwhaibi
    • , Sandeep Artham
    • , Arti Verma
    •  & Payaningal R. Somanath
  2. Charlie Norwood VA Medical Center, Augusta, GA, 30912, USA

    • Fei Gao
    • , Abdulrahman Alwhaibi
    • , Sandeep Artham
    • , Arti Verma
    •  & Payaningal R. Somanath
  3. Department of Urology, The First Affiliated Hospital, Chongqing University, Chongqing, China

    • Fei Gao
  4. Department of Medicine, Vascular Biology Center and Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA

    • Payaningal R. Somanath

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Contributions

Conception and design: F.G., A.A. and P.R.S.; data production, analysis and interpretation: F.G., A.A., S.A., A.V. and P.R.S.; writing the manuscript: F.G., A.A. and P.R.S. All authors reviewed the manuscript and accepted the content.

Competing interests

The authors declare no competing interests.

Availability of data and material

This study has no gene arrays or high-throughput screening. All the data related to the study are included within the article and the supplemental material.

Disclaimer

The funders had no role in the study design, data collection, analysis and decision to publish the data. The contents of the manuscript do not represent the views of Department of Veteran Affairs or the United States Government.

Corresponding author

Correspondence to Payaningal R. Somanath.

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DOI

https://doi.org/10.1038/s41416-018-0110-1