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Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer

Ack1：激素难治性前列腺癌的关键调节因子

基本信息

批准号：
8460126
负责人：
Nupam P Mahajan
金额：
$ 30.48万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-08 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460126
关键词：
Ablation Adenocarcinoma Affect Agar Age American Amino Acids Anchorage-Independent Growth Androgen Antagonists Androgen Receptor Androgens Antibodies Applications Grants Bicalutamide Binding Biological Biological Assay Cancer Etiology Cancer Patient Castration Cells Cessation of life ChIP-on-chip Data Development Disease EGF gene Enhancers Event Flutamide Gene Expression Gene Targeting Genes Genetic Transcription Growth Hormones Implant LAPC4 LNCaP Ligands Malignant - descriptor Malignant neoplasm of prostate Mediating Molecular Monitor Mus NKX3-1 gene Neoplasms Nude Mice Patients Phosphorylation Phosphotransferases Play Premalignant Prostate Prostatic Intraepithelial Neoplasias Protein Tyrosine Kinase Pyrimidine Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Refractory Research Proposals Reverse Transcriptase Polymerase Chain Reaction Role Staging Staining method Stains TMPRSS2 gene Testing Therapeutic Tissue Microarray Transactivation Transcriptional Activation Transgenic Mice Tyrosine Tyrosine Phosphorylation Xenograft procedure androgen independent prostate cancer castration resistant prostate cancer cell growth deprivation hormone refractory prostate cancer inhibitor/antagonist men mouse model pre-clinical probasin promoter receptor expression small molecule tumor growth tumor xenograft

项目摘要

ABSTRACT Androgen receptor (AR) plays a critical role in progression of prostate cancer. We have recently demonstrated that Ack1 (also known as TNK2) regulates AR Tyr267-phosphorylation within the transactivation domain. While AR transcriptional activation by multiple tyrosine kinases is emerging as an alternate mode of AR activation, the precise role of Ack1 mediated AR Tyr267- phosphorylation in AR recruitment to the androgen responsive enhancers (ARE) and androgen- independent AR-responsive gene transcription is not fully understood. In this grant proposal we demonstrate that activated Ack1(pTyr284-Ack1) expression is upregulated as prostate cancer progresses and this activation is inversely correlated with the survival of prostate cancer patients. Since Ack1 regulates androgen-independent AR activity by its phosphorylation at Tyr267, we generated antibodies that specifically recognize pTyr267-AR. Neither pTyr267-AR expression nor its transcriptional activation was affected by anti-androgens e.g. bicalutamide/casodex and flutamide. However, a small molecule inhibitor of Ack1, 4-Amino-5,6- biaryl-furo[2,3-d]pyrimidine (YL3-026) not only inhibited Ack1 activation, but was able to suppress pTyr267-AR phosphorylation, binding to PSA, NKX3.1 and TMPRS2 promoters and inhibit AR transcription activity as seen by significant decrease in PSA gene expression. Our evidence indicates that targeting Ack1 kinase in prostate cancer patients could therefore be highly effective therapeutic strategy. In this proposal we will determine how AR Tyr267- phosphorylation regulates Androgen-Independent growth. Further, we will examine the ability of Ack1 inhibitor, YL3-026, to suppress androgen-independent transcription and xenograft tumor formation. Moreover, we will assess the ability of Ack1 inhibitor YL3-026 to suppress AR Tyr267-phosphorylation and prostatic intraepithelial neoplasia (PINs) formation in Prob-Ack1 transgenic mice.

摘要