Elevated LIM kinase 1 in nonmetastatic prostate cancer reflects its role in facilitating androgen receptor nuclear translocation.

Abstract

Prostate cancer affects a large proportion of the male population, and is primarily driven by androgen receptor (AR) activity. First-line treatment typically consists of reducing AR signaling by hormone depletion, but resistance inevitably develops over time. One way to overcome this issue is to block AR function via alternative means, preferably by inhibiting protein targets that are more active in tumors than in normal tissue. By staining prostate cancer tumor sections, elevated LIM kinase 1 (LIMK1) expression and increased phosphorylation of its substrate Cofilin were found to be associated with poor outcome and reduced survival in patients with nonmetastatic prostate cancer. A LIMK-selective small molecule inhibitor (LIMKi) was used to determine whether targeted LIMK inhibition was a potential prostate cancer therapy. LIMKi reduced prostate cancer cell motility, as well as inhibiting proliferation and increasing apoptosis in androgen-dependent prostate cancer cells more effectively than in androgen-independent prostate cancer cells. LIMK inhibition blocked ligand-induced AR nuclear translocation, reduced AR protein stability and transcriptional activity, consistent with its effects on proliferation and survival acting via inhibition of AR activity. Furthermore, inhibition of LIMK activity increased αTubulin acetylation and decreased AR interactions with αTubulin, indicating that the role of LIMK in regulating microtubule dynamics contributes to AR function. These results indicate that LIMK inhibitors could be beneficial for the treatment of prostate cancer both by reducing nuclear AR translocation, leading to reduced proliferation and survival, and by inhibiting prostate cancer cell dissemination.

• Authors: Katerina Mardilovich, Mads Gabrielsen, Lynn McGarry, Clare Orange, Rachana Patel, Emma Shanks, Joanne Edwards, Michael F Olson
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 1 Pg. 246-58 (Jan 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25344584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• AR protein, human
• Actin Depolymerizing Factors
• Receptors, Androgen
• Small Molecule Libraries
• Tubulin
• LIMK1 protein, human
• LIMK2 protein, human
• Lim Kinases

Topics

• Actin Depolymerizing Factors (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lim Kinases (antagonists & inhibitors, genetics, metabolism)
• Male
• Prostatic Neoplasms (genetics, metabolism, mortality)
• Receptors, Androgen (genetics, metabolism)
• Small Molecule Libraries (pharmacology)
• Survival Analysis
• Tubulin (genetics, metabolism)