Abstract
Several studies have unraveled the negative role of Akt1 in advanced cancers, including metastatic prostate cancer (mPCa). Hence, understanding the consequences of targeting Akt1 in the mPCa and identifying its downstream novel targets is essential. We studied how Akt1 deletion in PC3 and DU145 cells activates the Nodal pathway and promotes PCa epithelial-to-mesenchymal transition (EMT) and metastasis. Here we show that Akt1 loss increases Nodal expression in PCa cells accompanied by activation of FoxO1/3a, and EMT markers Snail and N-cadherin as well as loss of epithelial marker E-cadherin. Treatment of PCa cells with FoxO inhibitor AS1842856 abrogated the Nodal expression in Akt1 deleted PCa cells. Akt1 deficient PCa cells exhibited enhanced cell migration and invasion
in vitro
and lung metastasis
in vivo
, which were attenuated by treatment with Nodal pathway inhibitor SB505124. Interestingly, Nodal mRNA analysis from two genomic studies in cBioportal showed a positive correlation between Nodal expression and Gleason score indicating the positive role of Nodal in human mPCa. Collectively, our data demonstrate Akt1-FoxO-Nodal pathway as an important mediator of PCa metastasis and present Nodal as a potential target to treat mPCa patients.
Prostate cancer cell Akt1 loss promotes epithelial-to-mesenchymal transition (EMT) via FoxO-mediated increased Nodal expression and ALK4/7 activation
in vitro
and metastasis to the mouse lungs.