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

Abstract：

: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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Mahajan NP,Liu Y,Majumder S,Warren MR,Parker CE,Mohler JL,Earp HS,Whang YE

doi

10.1073/pnas.0700420104

subject

Has Abstract

pub_date

2007-05-15 00:00:00

pages

8438-43

issue

eissn

0027-8424

issn

1091-6490

pii

0700420104

journal_volume

104

pub_type

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