Despite the reduced incidence and improved 5-year survival rate of localized PCa patients, there is a marked increase in the incidence of metastatic PCa (mPCa) and associated mortality. Decades of clinical trials targeting Akt oncogene for cancer have not yielded any desirable results. A growing body of evidence, including a prostate cancer study from our laboratory, have demonstrated that genetic or pharmacological Akt inhibition in the advanced cancers promotes metastasis. In our laboratory, although Akt1 deficiency in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice inhibited prostatic inter-epithelial neoplasia and tumor development, pharmacological suppression or genetic deletion of Akt1 in the advanced PCa promoted epithelial-to-mesenchymal transition (EMT) and metastasis. The overall objective of this thesis is to understand how Akt1 suppression mechanistically promotes PCa EMT and metastasis. First, our results from immunohistochemistry, as well as the cBioPortal patient genomic database analyses, demonstrated reduced Akt phosphorylation (activity) in high Gleason Score compared to low Gleason Score PCa tissues. Second, we identified that the promotion of PCa EMT with Akt1 gene deletion is due to increased Nodal expression. Pharmacological inhibition of Nodal pathway mitigated PCa EMT and metastasis in athymic nude mice. Genomic database analysis confirmed increased expression of TGF1 and Nodal in high Gleason Score compared to low Gleason Score PCa tissues. Third, we profiled the microRNAs and mRNAs comparing Akt1 intact with Akt1 deficient human PCa cells using the NanoString technology. We identified increased miR-199a-5p and decreased let-7a-5p in Akt1-silenced PCa cells correlating to the TGF1 pathway activation. Treatment of PCa cells with miR-199a-5p inhibitor and/or let-7a-5p mimic inhibited TGF-RI expression and affected their motility and invasion in vitro. Genomic data analysis from cBioPortal and Real-Time PCR analysis of human PCa tissues demonstrated elevated miR-199a-5p and reduced let-7a-5p in high vs. low Gleason Score tissues. Taken together, our study has demonstrated that targeting Akt1 in the advanced PCa promotes Nodal expression through FoxO and TGF pathway activation by microRNAs, presents FoxO and Nodal as two druggable targets for mPCa, and suggest that miR-199a-5p and let-7a-5p may potentially be targeted or utilized for the early detection of mPCa.