Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer

被引:74
作者
Liu, YB
Majumder, S
McCall, W
Sartor, CI
Mohler, JL
Gregory, CW
Earp, HS
Whang, YE
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA
[5] Univ N Carolina, Dept Surg, Chapel Hill, NC 27599 USA
[6] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA
[7] Roswell Pk Canc Ctr, Dept Urol Oncol, Buffalo, NY USA
关键词
D O I
10.1158/0008-5472.CAN-04-4292
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate All in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immuno-precipitation analysis, were impaired by RER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AIR function in prostate cancer.
引用
收藏
页码:3404 / 3409
页数:6
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