Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation.
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.
Mesh Terms:
Androgens, Animals, Cell Line, Tumor, DNA, Neoplasm, Disease Progression, Enhancer Elements, Genetic, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Models, Genetic, Mutation, Neuregulin-1, Phosphorylation, Phosphotyrosine, Prostatic Neoplasms, Protein Binding, Protein Transport, Protein-Tyrosine Kinases, Receptor, erbB-2, Receptors, Androgen, Transcription, Genetic, Transplantation, Heterologous
Androgens, Animals, Cell Line, Tumor, DNA, Neoplasm, Disease Progression, Enhancer Elements, Genetic, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Models, Genetic, Mutation, Neuregulin-1, Phosphorylation, Phosphotyrosine, Prostatic Neoplasms, Protein Binding, Protein Transport, Protein-Tyrosine Kinases, Receptor, erbB-2, Receptors, Androgen, Transcription, Genetic, Transplantation, Heterologous
Proc. Natl. Acad. Sci. U.S.A.
Date: May. 15, 2007
PubMed ID: 17494760
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