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



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.


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.


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.


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

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

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).


  1. 1.

    Dudley, A. C. Tumor endothelial cells. Cold Spring Harb. Perspect. Med. 2, a006536 (2012).

  2. 2.

    Weidner, N. New paradigm for vessel intravasation by tumor cells. Am. J. Pathol. 160, 1937–1939 (2002).

  3. 3.

    Wang, Z. et al. Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol. 35, S224–S243 (2015).

  4. 4.

    Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).

  5. 5.

    Cairns, P. et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 57, 4997–5000 (1997).

  6. 6.

    Goc, A. et al. PI3 kinase integrates Akt and MAP kinase signaling pathways in the regulation of prostate cancer. Int. J. Oncol. 38, 267–277 (2011).

  7. 7.

    Sabbineni, H. et al. Genetic deletion and pharmacological inhibition of Akt1 isoform attenuates bladder cancer cell proliferation, motility and invasion. Eur. J. Pharmacol. 764, 208–214 (2015).

  8. 8.

    Gao, F. et al. Suppression of Akt1-beta-catenin pathway in advanced prostate cancer promotes TGFβ1-mediated epithelial to mesenchymal transition and metastasis. Cancer Lett. 402, 177–189 (2017).

  9. 9.

    Goc, A. et al. Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis. BMC Cancer 12, 409 (2012).

  10. 10.

    Kochuparambil, S. T., Al-Husein, B., Goc, A., Soliman, S. & Somanath, P. R. Anticancer efficacy of simvastatin on prostate cancer cells and tumor xenografts is associated with inhibition of Akt and reduced prostate-specific antigen expression. J. Pharmacol. Exp. Ther. 336, 496–505 (2011).

  11. 11.

    Alhusban, A. et al. Clinically relevant doses of candesartan inhibit growth of prostate tumor xenografts in vivo through modulation of tumor angiogenesis. J. Pharmacol. Exp. Ther. 350, 635–645 (2014).

  12. 12.

    Al-Husein, B., Goc, A. & Somanath, P. R. Suppression of interactions between prostate tumor cell-surface integrin and endothelial ICAM-1 by simvastatin inhibits micrometastasis. J. Cell. Physiol. 228, 2139–2148 (2013).

  13. 13.

    Chen, J. et al. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat. Med. 11, 1188–1196 (2005).

  14. 14.

    Gao, F. et al. Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover. Cell. Mol. Life Sci. 73, 3917–3933 (2016).

  15. 15.

    Somanath, P. R., Vijai, J., Kichina, J. V., Byzova, T. & Kandel, E. S. The role of PAK-1 in activation of MAP kinase cascade and oncogenic transformation by Akt. Oncogene 28, 2365–2369 (2009).

  16. 16.

    Goc, A. et al. P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor beta expression and enhanced matrix metalloproteinase 9 secretion. J. Biol. Chem. 288, 3025–3035 (2013).

  17. 17.

    Abdalla, M., Goc, A., Segar, L. & Somanath, P. R. Akt1 mediates alpha-smooth muscle actin expression and myofibroblast differentiation via myocardin and serum response factor. J. Biol. Chem. 288, 33483–33493 (2013).

  18. 18.

    Goc, A. et al. Targeting Src-mediated Tyr216 phosphorylation and activation of GSK-3 in prostate cancer cells inhibit prostate cancer progression in vitro and in vivo. Oncotarget 5, 775–787 (2014).

  19. 19.

    Gao, F., Al-Azayzih, A. & Somanath, P. R. Discrete functions of GSK3α and GSK3β isoforms in prostate tumor growth and micrometastasis. Oncotarget 6, 5947–5962 (2015).

  20. 20.

    Trani, M. & Dejana, E. New insights in the control of vascular permeability: vascular endothelial-cadherin and other players. Curr. Opin. Hematol. 22, 267–272 (2015).

  21. 21.

    Gao, F., Sabbineni, H., Artham, S. & Somanath, P. R. Modulation of long-term endothelial-barrier integrity is conditional to the cross-talk between Akt and Src signaling. J. Cell. Physiol. 232, 2599–2609 (2017).

  22. 22.

    Dejana, E., Orsenigo, F. & Lampugnani, M. G. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J. Cell Sci. 121(Pt 13), 2115–2122 (2008).

  23. 23.

    Taddei, A. et al. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat. Cell Biol. 10, 923–934 (2008).

  24. 24.

    Gavard, J., Patel, V. & Gutkind, J. S. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev. Cell 14, 25–36 (2008).

  25. 25.

    Gavard, J. & Gutkind, J. S. VE-cadherin and claudin-5: it takes two to tango. Nat. Cell Biol. 10, 883–885 (2008).

  26. 26.

    Jonasch, E. et al. A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. Ann. Oncol. 28, 804–808 (2017).

  27. 27.

    Chung, V. et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 3, 516–522 (2017).

  28. 28.

    Ahn, D. H. et al. Results of an abbreviated phase-II study with the Akt inhibitor MK-2206 in patients with advanced biliary cancer. Sci. Rep. 5, 12122 (2015).

  29. 29.

    Ramanathan, R. K. et al. Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: a SWOG cooperative group trial (S1005). Cancer 121, 2193–2197 (2015).

  30. 30.

    Konopleva, M. Y. et al. Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. Clin. Cancer Res. 20, 2226–2235 (2014).

  31. 31.

    Do, K. et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest. New Drugs 33, 720–728 (2015).

  32. 32.

    Stamos, J. L. & Weis, W. I. The beta-catenin destruction complex. Cold Spring Harb. Perspect. Biol. 5, a007898 (2013).

  33. 33.

    Al Thawadi, H. et al. VE-cadherin cleavage by ovarian cancer microparticles induces beta-catenin phosphorylation in endothelial cells. Oncotarget 7, 5289–5305 (2016).

  34. 34.

    Byzova, T. V. et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol. Cell 6, 851–860 (2000).

  35. 35.

    Senger, D. R. et al. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev. 12, 303–324 (1993).

  36. 36.

    Singleton, P. A. et al. Akt-mediated transactivation of the S1P1 receptor in caveolin-enriched microdomains regulates endothelial barrier enhancement by oxidized phospholipids. Circ. Res. 104, 978–986 (2009).

  37. 37.

    Mukai, Y. et al. Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt. J. Clin. Invest. 116, 334–343 (2006).

  38. 38.

    De Palma, C., Meacci, E., Perrotta, C., Bruni, P. & Clementi, E. Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: a novel pathway relevant to the pathophysiology of endothelium. Arterioscler. Thromb. Vasc. Biol. 26, 99–105 (2006).

  39. 39.

    Daly, C. et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev. 18, 1060–1071 (2004).

  40. 40.

    Jones, C. A. et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat. Med. 14, 448–453 (2008).

  41. 41.

    Tejeda-Munoz, N. & Robles-Flores, M. Glycogen synthase kinase 3 in Wnt signaling pathway and cancer. IUBMB Life 67, 914–922 (2015).

  42. 42.

    Wang, Q. et al. Spontaneous hepatocellular carcinoma after the combined deletion of Akt isoforms. Cancer Cell 29, 523–535 (2016).

  43. 43.

    Li, C. W. et al. AKT1 inhibits epithelial-to-mesenchymal transition in breast cancer through phosphorylation-dependent Twist1 degradation. Cancer Res. 76, 1451–1462 (2016).

  44. 44.

    Iliopoulos, D. et al. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci. Signal. 2, ra62 (2009).

  45. 45.

    Rao, G. et al. Inhibition of AKT1 signaling promotes invasion and metastasis of non-small cell lung cancer cells with K-RAS or EGFR mutations. Sci. Rep. 7, 7066 (2017).

Download references


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

Author information


  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


  1. Search for Fei Gao in:

  2. Search for Abdulrahman Alwhaibi in:

  3. Search for Sandeep Artham in:

  4. Search for Arti Verma in:

  5. Search for Payaningal R. Somanath in:


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.

Funds were provided by the National Institutes of Health grant (R01HL103952) to P.R.S.

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.


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.

Electronic supplementary material

About this article

Publication history