Endothelial Akt1 loss promotes prostate cancer metastasis via \u03b2-catenin-regulated tight-junction protein turnover

Arti Verma,Payaningal R Somanath,Abdulrahman Alwhaibi,Fei Gao,Sandeep Artham

doi:10.1038/s41416-018-0110-1

Abstract

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

Highlights

Research in the development of cancer therapy more focused on the pathways promoting tumour cell growth and invasion
We demonstrated that endothelial-specific knockdown of Akt[1] results in increased vascular permeability via FoxO- and β-catenin-mediated suppression of endothelial tight-junction claudin expression, mainly claudin-5.14 Since many inhibitors of Akt are in different phases of clinical trials for various types of cancers, it is important to understand the effect of Akt[1] suppression in endothelial cells of tumour vasculature, and its consequences on tumour growth and metastasis
Our analysis revealed that Akt[1] deficiency in human lung microvascular endothelial cells (HLECs) enhances the ability of human metastatic PC3 and DU145 prostate cancer cells to migrate across the endothelial monolayer in vitro, and murine RM1 prostate cancer cell metastasis to the lungs in vivo, with no changes in the growth of RM1 tumour xenografts in vivo

Summary

Introduction

Research in the development of cancer therapy more focused on the pathways promoting tumour cell growth and invasion. In general, is focused on targeting tumour cells to limit tumour growth These studies, do not account for the specific effects of chemotherapy on tumour endothelium, in turn, affecting metastasis. CONCLUSIONS: Here we show for the first time that endothelial-specific loss of Akt[1] promotes cancer metastasis in vivo involving β-catenin pathway

Methods

Results

Conclusion