Journal Article

Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation

Mahajan, Nupam P, Liu, Yuanbo, Parker, Carol E, Mohler, James L, Earp, H. Shelton, Majumder, Samarpan, Whang, Young E, Warren, Maria R

2007

Overview

Activation of the androgen receptor (AR) may play a role in androgen-independent progression of prostate cancer. Multiple mechanisms of AR activation, including stimulation by tyrosine kinases, have been postulated. We and others have recently shown involvement of activated Cdc42-associated tyrosine kinase Ack1 in advanced human prostate cancer. Here we provide the molecular basis for interplay between Ack1 and AR in prostate cancer cells. Activated Ack1 promoted androgen-independent growth of LNCaP and LAPC-4 prostate xenograft tumors, AR recruitment to the androgen-responsive enhancer, and androgen-inducible gene expression in the absence of androgen. Heregulin-stimulated HER2 activation induced Ack1 activation and AR tyrosine phosphorylation. Ack1 knockdown inhibited heregulin-dependent AR tyrosine phosphorylation, AR reporter activity, androgen-stimulated gene expression, and AR recruitment. Ack1 was recruited to the androgen-responsive enhancers after androgen and heregulin stimulation. In 8 of 18 primary androgen-independent prostate tumor samples, tyrosine-phosphorylated AR protein was detected and correlated with the detection of tyrosine-phosphorylated Ack1. Neither was elevated in androgen-dependent tumors or benign prostate samples. Activated Ack1 phosphorylated AR protein at Tyr-267 and Tyr-363, both located within the transactivation domain. Mutation of Tyr-267 completely abrogated and mutation of Tyr-363 reduced Ack1-induced AR reporter activation and recruitment of AR to the androgen-responsive enhancer. Expression of AR point mutants inhibited Ack1-driven xenograft tumor growth. Thus, Ack1 activated by surface signals or oncogenic mechanisms may directly enhance AR transcriptional function and promote androgen-independent progression of prostate cancer. Targeting the Ack1 kinase may be a potential therapeutic strategy in prostate cancer.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: androgen receptors / Androgens / Androgens - pharmacology / Animals / Antibodies / Biochemistry / Biological Sciences / Cell Line, Tumor / Cells / Disease Progression / DNA, Neoplasm - metabolism / Enhancer Elements, Genetic - genetics / Enzyme Activation - drug effects / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Genetic mutation / Heterologous transplantation / Humans / Kinases / Male / Mice / Models, Genetic / mutants / Mutation / Mutation - genetics / neoplasm cells / Neuregulin-1 - metabolism / Phosphorylation / Phosphorylation - drug effects / phosphotransferases (kinases) / Phosphotyrosine - metabolism / Prostate / Prostate cancer / prostatic neoplasms / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Protein Binding - drug effects / Protein Transport - drug effects / Protein-Tyrosine Kinases - genetics / Protein-Tyrosine Kinases - metabolism / Receptor, ErbB-2 - metabolism / Receptors, Androgen - chemistry / Receptors, Androgen - metabolism / Signal transduction / Small interfering RNA / transcription (genetics) / Transcription, Genetic - drug effects / transcriptional activation / Transplantation, Heterologous / Tumors / tyrosine