The long-term goal of this project is to understand the molecular mechanisms of hormone-independent growth and metastasis of prostate cancer (PCA). Our preliminary data demonstrates, for the first time, that tyrosine phosphorylation of the androgen receptor (AR) and its cofactor p300 is associated with hormone refractory growth of PCA cells, suggesting that the hormone refractory tumor cells may utilize autocrine/paracrine factors activating tyrosine kinases in the tumor cells to compensate the loss of androgens under the circumstance of androgen ablation therapy. Several lines of evidence suggest an important role of tyrosine kinase Etk in this process. Etk is up-regulated in over 50% of PCA specimens examined. Etk kinase activity is negatively regulated by tumor suppressors PTEN and p53. The expression level of IL6 and Etk in mouse prostates is elevated in response to castration. The kinase activity of Etk is required for androgen-independent activation of the androgen receptor (AR) by several non-steroid stimuli including IL6, bombesin and neurotensin. The siRNA specific for Etk reduces growth factor-induced tyrosine phosphorylation of AR and inhibits PCA cell proliferation. Overexpression of Etk in PCA cells results in increased expression of the nuclear receptor coactivator p300 which is essential for AR-mediated transcription. Furthermore, targeted expression of Etk in mouse prostate gland results in pathological changes resembling prostatic intraepithelial neoplasia (PIN) and a delayed apoptotic response to castration. We therefore hypothesize that Etk is a key mediator in IL6 signaling in PCA cells and plays an important role in the development of hormone refractory PCA by directly phosphorylating AR and modulating nuclear cofactor p300 activity, leading to activation of AR independent of androgens or sensitization of AR to low levels of androgens.
Our aims are:
Aim 1 : To elucidate the mechanisms underlying the growth factor-induced tyrosine phosphorylation of AR in PCA cells. The effects of tyrosine phosphorylation of AR on its ligand binding activity, its N/C- terminal interaction and the recruitment of its co- factors will be investigated. The contribution of tyrosine phosphorylation of AR to the growth of hormone refractory PCA cells will be assessed by an """"""""AR Replacement"""""""" strategy established in our laboratory. Furthermore, the role of Etk and possibly other tyrosine kinases in growth factor-induced tyrosine phosphorylation of AR will be studied.
Aim 2 : To investigate the role of Etk in modulation of nuclear cofactor p300 activity in PCA cells. The mechanisms by which Etk regulates the promoter activity of p300 will be studied. The tyrosine phosphorylation site of p300 induced by Etk will be identified. Furthermore, the contribution of tyrosine phosphorylation of p300 to its acetyltransferase activity and the AR-mediated transcription activity as well as the hormone-independent growth of PCA cells will be investigated.
Aim 3 : To study the role of Etk in the development of hormone-independence in mouse models. Compound mice which carry multiple genetic modifications will be generated on the Etk transgenic background to study the interaction of Etk with tumor suppressor PTEN in the mouse prostate and their roles in development of hormone-independence in the mouse prostate. Comparative microarray analysis will be performed to reveal the altered gene expression in the Etk transgenic and the compound mice in response to castration, which may lead to discovery of the genes involved in development of hormone-independence.
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|Xu, Jin; Qiu, Yun (2016) Role of androgen receptor splice variants in prostate cancer metastasis. Asian J Urol 3:177-184|
|Deshmukh, Dhanraj; Qiu, Yun (2015) Role of PARP-1 in prostate cancer. Am J Clin Exp Urol 3:1-12|
|Sun, Feng; Chen, He-ge; Li, Wei et al. (2014) Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J Biol Chem 289:1529-39|
|Linn, Douglas E; Yang, Xi; Xie, Yingqiu et al. (2012) Differential regulation of androgen receptor by PIM-1 kinases via phosphorylation-dependent recruitment of distinct ubiquitin E3 ligases. J Biol Chem 287:22959-68|
|Guo, Zhiyong; Qiu, Yun (2011) A new trick of an old molecule: androgen receptor splice variants taking the stage?! Int J Biol Sci 7:815-22|
|Guo, Shengjie; Sun, Feng; Guo, Zhiyong et al. (2011) Tyrosine kinase ETK/BMX is up-regulated in bladder cancer and predicts poor prognosis in patients with cystectomy. PLoS One 6:e17778|
|Yang, Xi; Guo, Zhiyong; Sun, Feng et al. (2011) Novel membrane-associated androgen receptor splice variant potentiates proliferative and survival responses in prostate cancer cells. J Biol Chem 286:36152-60|
|Dai, Bojie; Chen, Hege; Guo, Shengjie et al. (2010) Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells. Cancer Res 70:5587-96|
|Xie, Yingqiu; Burcu, Mehmet; Linn, Douglas E et al. (2010) Pim-1 kinase protects P-glycoprotein from degradation and enables its glycosylation and cell surface expression. Mol Pharmacol 78:310-8|
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