PIP5K1? is Required for Promoting Tumor Progression in Castration-Resistant Prostate Cancer

PIP5K1? has emerged as a promising drug target for the treatment of castration-resistant prostate cancer (CRPC), as it acts upstream of the PI3K/AKT signaling pathway to promote prostate cancer (PCa) growth, survival and invasion. However, little is known of the molecular actions of PIP5K1? in this process. Here, we show that siRNA-mediated knockdown of PIP5K1? and blockade of PIP5K1? action using its small molecule inhibitor ISA-2011B suppress growth and invasion of CRPC cells. We demonstrate that targeted deletion of the N-terminal domain of PIP5K1? in CRPC cells results in reduced growth and migratory ability of cancer cells. Further, the xenograft tumors lacking the N-terminal domain of PIP5K1? exhibited reduced tumor growth and aggressiveness in xenograft mice as compared to that of controls. The N-terminal domain of PIP5K1? is required for regulation of mRNA expression and protein stability of PIP5K1?. This suggests that the expression and oncogenic activity of PIP5K1? are in part dependent on its N-terminal domain. We further show that PIP5K1? acts as an upstream regulator of the androgen receptor (AR) and AR target genes including CDK1 and MMP9 that are key factors promoting growth, survival and invasion of PCa cells. ISA-2011B exhibited a significant inhibitory effect on AR target genes including CDK1 and MMP9 in CRPC cells with wild-type PIP5K1? and in CRPC cells lacking the N-terminal domain of PIP5K1?. These results indicate that the growth of PIP5K1?-dependent tumors is in part dependent on the integrity of the N-terminal sequence of this kinase. Our study identifies a novel functional mechanism involving PIP5K1?, confirming that PIP5K1? is an intriguing target for cancer treatment, especially for treatment of CRPC.