www.nature.com/bjc ARTICLE Translational Therapeutics Endothelial Akt1 loss promotes prostate cancer metastasis via β-catenin-regulated tight-junction protein turnover 1,2,3 1,2 1,2 1,2 1,2,4 Fei Gao , Abdulrahman Alwhaibi , Sandeep Artham , Arti Verma and Payaningal R. Somanath 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
British Journal of Cancer – Springer Journals
Published: May 14, 2018
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