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

British Journal of Cancer
Fei GaoPayaningal R Somanath

Abstract

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 fir...Continue Reading

References

Sep 1, 1993·Cancer Metastasis Reviews·D R SengerH F Dvorak
Jun 12, 2002·The American Journal of Pathology·Noel Weidner
Feb 3, 2006·The Journal of Clinical Investigation·Yasushi MukaiJames K Liao
Jun 21, 2008·Journal of Cell Science·Elisabetta DejanaMaria Grazia Lampugnani
Aug 2, 2008·Nature Cell Biology·Julie Gavard, J Silvio Gutkind
Oct 15, 2009·Science Signaling·Dimitrios IliopoulosPhilip N Tsichlis
Nov 10, 2010·The Journal of Pharmacology and Experimental Therapeutics·Samith T KochuparambilPayaningal R Somanath
Mar 7, 2012·Cold Spring Harbor Perspectives in Medicine·Andrew C Dudley
Nov 22, 2012·Cold Spring Harbor Perspectives in Biology·Jennifer L Stamos, William I Weis
Oct 10, 2013·The Journal of Biological Chemistry·Maha AbdallaPayaningal R Somanath
Mar 4, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Marina Y KonoplevaHagop M Kantarjian
Jul 6, 2014·The Journal of Pharmacology and Experimental Therapeutics·Ahmed AlhusbanPayaningal R Somanath
Jan 21, 2015·Seminars in Cancer Biology·Zongwei WangLasse D Jensen
Mar 15, 2015·Current Opinion in Hematology·Marianna Trani, Elisabetta Dejana
Nov 26, 2015·IUBMB Life·Nydia Tejeda-Muñoz, Martha Robles-Flores
Apr 27, 2016·Cellular and Molecular Life Sciences : CMLS·Fei GaoPayaningal R Somanath

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Citations

Feb 20, 2020·American Journal of Physiology. Lung Cellular and Molecular Physiology·Sandeep ArthamPayaningal R Somanath
Nov 18, 2018·Cell Communication and Signaling : CCS·Wei LiSong-Qiang Xie
Jul 24, 2020·Canadian Journal of Physiology and Pharmacology·Asma GahPayaningal R Somanath
Dec 11, 2020·Tissue Barriers·Mir S AdilPayaningal R Somanath
Dec 26, 2018·Journal of Cellular Biochemistry·Yuemei YangWeiliang Ye
Dec 8, 2020·Analytical Cellular Pathology (Amsterdam)·Bangbin ChenXuewen Xu
Aug 23, 2021·Journal of Hematology & Oncology·Hui HuaYangfu Jiang

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Datasets Mentioned

BETA
GM-2

Methods Mentioned

BETA
xenograft
gene knockout
xenografts
nuclear translocation
transgenic
transfection
protein assay
PCR

Software Mentioned

GraphPad Prism
SPSS
ARRIVE

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