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：
8246962
负责人：
Nupam P Mahajan
金额：
$ 32.85万
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/8246962
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 Resistance 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 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.

抽象的雄激素受体（AR）在前列腺癌的进展中起关键作用。我们最近有证明ACK1（也称为TNK2）调节AR Tyr267-磷酸化反式激活域。而多种酪氨酸激酶的AR转录激活是作为AR激活的一种替代模式，ACK1介导的AR Tyr267-的精确作用 AR募集到雄激素响应增强子（AR）和雄激素（雄激素）的磷酸化独立的AR响应基因转录尚不完全了解。在这个赠款建议中我们证明活化的ACK1（PTYR284-ACK1）表达被上调为前列腺癌进展，这种激活与前列腺癌的存活率成反比患者。由于ACK1通过其磷酸化调节雄激素非依赖性AR活性 Tyr267，我们生成了专门识别PTYR267-AR的抗体。 ptyr267-ar都不是表达和转录激活受抗雄激素的影响，例如 Bicalutamide/casodex和Flutamide。但是，ACK1的小分子抑制剂，4-氨基-5,6-- Biaryl-Furo [2,3-D]嘧啶（YL3-026）不仅抑制ACK1激活，而且能够抑制抑制PTYR267-AR磷酸化，与PSA，NKX3.1和TMPRS2启动子结合，以及抑制AR转录活性，如PSA基因表达的显着降低所见。我们的证据表明，在前列腺癌患者中靶向ACK1激酶可能是高效的治疗策略。在此提案中，我们将确定如何Ar Tyr267- 磷酸化调节雄激素非依赖性生长。此外，我们将研究 ACK1抑制剂YL3-026，以抑制独立的转录和异种移植肿瘤形成。此外，我们将评估ACK1抑制剂YL3-026抑制AR的能力在Prob-Ack1中转基因小鼠。