Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells.

Abstract

We previously showed that targeted expression of non-receptor tyrosine kinase Etk/BMX in mouse prostate induces prostate intraepithelial neoplasia, implying a possible causal role of Etk in prostate cancer development and progression. Here, we report that Etk is upregulated in both human and mouse prostates in response to androgen ablation. Etk expression seems to be differentially regulated by androgen and interleukin 6 (IL-6), which is possibly mediated by the androgen receptor (AR) in prostate cancer cells. Our immunohistochemical analysis of tissue microarrays containing 112 human prostate tumor samples revealed that Etk expression is elevated in hormone-resistant prostate cancer and positively correlated with tyrosine phosphorylation of AR (Pearson correlation coefficient rho = 0.71, P < 0.0001). AR tyrosine phosphorylation is increased in Etk-overexpressing cells, suggesting that Etk may be another tyrosine kinase, in addition to Src and Ack-1, which can phosphorylate AR. We also showed that Etk can directly interact with AR through its Src homology 2 domain, and such interaction may prevent the association of AR with Mdm2, leading to stabilization of AR under androgen-depleted conditions. Overexpression of Etk in androgen-sensitive LNCaP cells promotes tumor growth while knocking down Etk expression in hormone-insensitive prostate cancer cells by a specific shRNA that inhibits tumor growth under androgen-depleted conditions. Taken together, our data suggest that Etk may be a component of the adaptive compensatory mechanism activated by androgen ablation in prostate and may play a role in hormone resistance, at least in part, through direct modulation of the AR signaling pathway.

• Authors: Bojie Dai, Hege Chen, Shengjie Guo, Xi Yang, Douglas E Linn, Feng Sun, Wei Li, Zhiyong Guo, Kexin Xu, Oekyung Kim, Xiangtian Kong, Jonathan Melamed, Shaopeng Qiu, Hegang Chen, Yun Qiu
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 13 Pg. 5587-96 (Jul 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20570899 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2010 AACR.

Chemical References

• Androgen Antagonists
• Androgens
• Receptors, Androgen
• BMX protein, human
• Bmx protein, mouse
• Protein-Tyrosine Kinases

Topics

• Androgen Antagonists (therapeutic use)
• Androgens (deficiency)
• Animals
• COS Cells
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Chlorocebus aethiops
• Humans
• Male
• Mice
• Neoplasms, Hormone-Dependent (enzymology, metabolism, pathology)
• Orchiectomy
• Prostatic Neoplasms (enzymology, metabolism, pathology, therapy)
• Protein-Tyrosine Kinases (biosynthesis, metabolism)
• Receptors, Androgen (metabolism)
• Up-Regulation