Effect of Ack1 tyrosine kinase inhibitor on ligand‐independent androgen receptor activity

Abstract

Background Androgen receptor (AR) plays a critical role in the progression of both androgen-dependent and androgen-independent prostate cancer (AIPC). Ligand-independent activation of AR in AIPC or castration resistant prostate cancer (CRPC) is often associated with poor prognosis. Recently, tyrosine kinase Ack1 has been shown to regulate AR activity by phosphorylating it at tyrosine 267 and this event was shown to be critical for AIPC growth. However, whether a small molecule inhibitor that can mitigate Ack1 activation is sufficient to abrogate AR activity on AR regulated promoters in androgen-depleted environment is not known. Methods We have generated two key resources, antibodies that specifically recognize pTyr267-AR and synthesized a small molecule inhibitor of Ack1, 4-amino-5,6-biaryl-furo[2,3-d]pyrimidine (named here as AIM-100) to test whether AIM-100 modulates ligand-independent AR activity and inhibits prostate cell growth. Results Prostate tissue microarray analysis indicates that Ack1 Tyr284 phosphorylation correlates positively with disease progression and negatively with the survival of prostate cancer patients. Interestingly, neither pTyr267-AR expression nor its transcriptional activation was affected by anti-androgens in activated Ack1 expressing or EGF stimulated prostate cells. However, the Ack1 inhibitor, AIM-100, not only inhibited Ack1 activation but also able to suppress pTyr267-AR phosphorylation, binding of AR to PSA, NKX3.1, and TMPRSS2 promoters, and inhibit AR transcription activity. Conclusion Ack1 Tyr284 phosphorylation is prognostic of progression of prostate cancer and inhibitors of Ack1 activity could be novel therapeutic agents to treat AIPC.

ACK1 promotes hepatocellular carcinoma progression via downregulating WWOX and activating AKT signaling

“…ACK1, an intracellular tyrosine kinase, is considered to be implicated in regulating multiple aspects of tumor progression (13,16). Several studies have indicated that ACK1 overexpression is commonly observed in human cancers including lung and prostate cancer (27,33). Furthermore, it has been demonstrated that ACK1 can promote tumor growth via regulating pro-survival molecules such as AKT and AR in various cancers (26,31,33).…”

“…Several studies have indicated that ACK1 overexpression is commonly observed in human cancers including lung and prostate cancer (27,33). Furthermore, it has been demonstrated that ACK1 can promote tumor growth via regulating pro-survival molecules such as AKT and AR in various cancers (26,31,33). The role of ACK1 have been investigated in multiple tumor types (31,33).…”

“…Furthermore, it has been demonstrated that ACK1 can promote tumor growth via regulating pro-survival molecules such as AKT and AR in various cancers (26,31,33). The role of ACK1 have been investigated in multiple tumor types (31,33). However, the ACK1 expression and its related molecule mechanisms in HCC remained unknown.…”

Regulation of the androgen receptor by post-translational modifications

“…EGF and Gas6 can also result in Tyr267 phosphorylation (Liu et al 2010b). Anti-androgens have no effect on tyrosine phosphorylation at 267 (Mahajan et al 2010); however, inhibition can be achieved using Dasatinib, a Src and Ack1 inhibitor (Liu et al 2010b). The AR isoform, AR8, has recently been identified.…”

Activated Cdc42-associated Kinase 1 (Ack1) Is Required for Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Receptor Recruitment to Lipid Rafts and Induction of Cell Death

“…Ack1 has been reported to either promote clathrin-mediated endocytosis of EGFR and target it for degradation (23,24) or, conversely, to stabilize cell surface expression of EGFR (25), suggesting different functions for Ack1 in different cell types. Ack1 has also been reported to regulate the receptor tyrosine kinase Axl and the androgen receptor (22,26) and to interact with a number of molecules involved in vesicular trafficking, including clathrin, AP2 (adaptor protein 2), and SNX9 (sorting nexin 9) (27)(28)(29).…”