Pleckstrin-2 Mediates the Activation of AKT in Prostate Cancer and Is Repressed by Androgen Receptor

Abstract

PI3K-AKT and androgen receptor (AR) pathways are commonly activated in prostate cancers. Their reciprocal regulation makes it difficult to treat advanced prostate cancers. Here, we show that Pleckstrin-2 (PLEK2), a proto-oncoprotein involved in the activation and stabilization of AKT, connects these two pathways. We first provide genetic evidence that Plek2 deficiency largely reverted tumorigenesis in Pten prostate-specific knockout mice. Overexpression of PLEK2 promotes the proliferation and colony formation of prostate cancer cells in vitro. In addition, we found that PLEK2 is negatively regulated by AR. AR transcriptionally represses PLEK2 through binding to the PLEK2 promoter region. Overexpression of AR reduces PLEK2 expression, which inactivates AKT. Conversely, knockdown of AR in prostate cancer cells increases PLEK2 expression and activates the AKT pathway. This reciprocal inhibitory loop can be pharmacologically targeted using the PLEK2 inhibitor. We show that the PLEK2 inhibitor dose-dependently inhibits prostate cancer cell proliferation with the inactivation of AKT. Overall, our study uncovers the critical role of PLEK2 in prostate cancer proliferation and provides the rationale for targeting PLEK2 to treat prostate cancers.