Targeted suppression of AR-V7 using PIP5K1α inhibitor overcomes enzalutamide resistance in prostate cancer cells

Abstract

One mechanism of resistance of prostate cancer (PCa) to enzalutamide (MDV3100) treatment is the increased expression of AR variants lacking the ligand binding-domain, the best characterized of which is AR-V7. We have previously reported that Phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), is a lipid kinase that links to CDK1 and AR pathways. The discovery of PIP5Kα inhibitor highlight the potential of PIP5K1α as a drug target in PCa. In this study, we show that AR-V7 expression positively correlates with PIP5K1α in tumor specimens from PCa patients. Overexpression of AR-V7 increases PIP5K1α, promotes rapid growth of PCa in xenograft mice, whereas inhibition of PIP5K1α by its inhibitor ISA-2011B suppresses the growth and invasiveness of xenograft tumors overexpressing AR-V7. PIP5K1α is a key co-factor for both AR-V7 and AR, which are present as protein-protein complexes predominantly in the nucleus of PCa cells. In addition, PIP5K1α and CDK1 influence AR-V7 expression also through AKT-associated mechanism dependent on PTEN-status. ISA-2011B disrupts protein stabilization of AR-V7 which is dependent on PIP5K1α, leading to suppression of invasive growth of AR-V7-high tumors in xenograft mice. Our study suggests that combination of enzalutamide and PIP5K1α may have a significant impact on refining therapeutic strategies to circumvent resistance to antiandrogen therapies.

Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer

“…Recent high-throughput RNAi screening identified checkpoint kinase 2 ( CHK2 ) as a tumour suppressor in PCa; CHK2 negatively regulates CDK1, forming a signalling loop with AR ( Ta et al , 2015 ). Furthermore, AR-V7 interacts with CDK1 and phosphatidylinositol-4-phosphate 5-kinase alpha to induce metastatic growth and treatment resistance ( Sarwar et al , 2016 ). Therefore, CDK1 inhibitors may be promising novel CRPC therapeutics.…”

Development of an in vitro screening assay for PIP5K1α lipid kinase and identification of potent inhibitors

“…The AR is normally activated by DHT, a testosterone derivative synthesized by 5aR. It was shown by Sarwar et al [11] that PIP5K1a additionally binds to AR and the constitutively active AR variant V7 promoting protein stability leading to cancer progression. Inhibition of AKT by pleckstrin homology domain and leucine-rich repeat protein phosphatase and its chaperone FK506 binding protein 5 and inhibition of the receptor tyrosine-protein kinase erbB-2/3 (HER2/HER3) by mTOR lead to a reciprocal feedback mechanism between PI3K/AKT/mTOR and AR signaling as described by Carver et al in mice with PTEN-deficient tumors [20].…”

“…A recently reported study revealed that binding of ISA-2011B to PIP5K1a interrupts the AR/PIP5K1a protein complex and thus makes it more accessible for proteasome-dependent degradation. This could be an indication that ISA-2011B acts as a destabilizing agent to reduce PIP5K1a expression level in PCa cells, and not via reducing the activity on the enzymatic level [11].…”

“…hPIP5K1a is overexpressed in highgrade PCa, and its overexpression is associated with an increased amount of PIP 2 [10]. Besides its role upstream of PI3K in PI3K/AKT/mTOR signaling, hPIP5K1a was also proven to interact with the androgen receptor (AR) [11]. The androgen testosterone is synthesized in the testis and in the adrenal and subsequently transported to prostate tissues where it is converted to 5a-dihydrotestosterone (DHT) by a 5areductase (5aR).…”

“…One mechanism for adaptation of PCa to androgen deprivation is increased expression of the constitutively active AR variant V7 [18,19]. hPIP5K1a was shown to form protein complexes with AR-V7, leading to protein stabilization by prevention of proteasome-dependent degradation [11]. Carver et al showed the existence of a reciprocal feedback mechanism between PI3K/AKT/mTOR and AR signaling.…”