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 LIMKselective 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 androgendependent prostate cancer cells more effectively than in androgenindependent 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 aTubulin acetylation and decreased AR interactions with aTubulin, 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.

Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3

“…To the best of our knowledge, previous investigations addressing LIMK in the prostate were limited to an oncological context (Misra et al ., ; Mardilovich et al ., ). Our findings suggest LIMK1 and −2 are expressed in the hyperplastic human prostate, and this may increase with the degree of BPH.…”

“…This LIMK‐dependent actin organization requires the phosphorylation of cofilin by LIMK (Yang et al ., ; Maekawa et al ., ; Mouneimne et al ., ; Bernard, ; Scott et al ., ; Mardilovich et al ., ). Consequently, LIMK has been reported to regulate several actin‐dependent functions, including migration, motility and chemotaxis, as well as proliferation (Mouneimne et al ., ; Li et al ., ; Yin et al ., ; Mardilovich et al ., ,b; Kapur et al ., ). As smooth muscle contraction requires actin organization and LIMK‐dependent actin organization has been reported in vascular smooth muscle cells, it is assumed LIMK is involved in smooth muscle contraction (San Martin et al ., ; Hennenberg et al ., ).…”

LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers

“…Independently of this effect on actin microfilament dynamics, LIMKs regulate microtubule dynamics (2-4), but whether this regulation occurs through a direct binding of LIMK to microtubules (5) or through phosphorylation of an associated protein (6) is still under debate. When LIMKs are inhibited, microtubules are stabilized and actin microfilaments are severed and disorganized (2,4).…”

“…The activation of the Rho-GTPases and their effectors, including LIMK, have been reported as playing important roles in tumor development and progression (8)(9)(10)(11)(12)(13). Expression of LIMK or cofilin phosphorylation is elevated in malignant melanoma (14), glioma (15), prostate (4,16,17), and breast tumors (18,19). In breast cancer models, activation of LIMK is the last step of an integrin-linked machinery of cytoskeletal regulation that enables tumor initiation and metastatic colonization (20).…”

Targeting LIM kinases in taxane resistant tumors

“…LIMKs regulate the architecture of the actin cytoskeleton by phosphorylation and inactivation of actin depolymerization factors of the ADF/cofilin family. Independently of this effect on actin microfilament dynamics, LIMKs also regulate microtubule dynamics, but whether this regulation occurs through a direct binding of LIMK to microtubules or through phosphorylation of an associated protein is still unknown [3, 4]. When LIMKs are inhibited, microtubules are stabilized and actin microfilaments are severed.…”