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

Abstract

BACKGROUND AND PURPOSEIn men with benign prostatic hyperplasia, increased smooth muscle tone in the prostate may lead to bladder outlet obstruction and subsequent lower urinary tract symptoms. Consequently, medical treatment aims to inhibit prostate smooth muscle contraction. However, the efficacy of the treatment options available is limited, and improved understanding of mechanisms of prostate smooth muscle contraction and identification of new targets for medical intervention are mandatory. Several studies suggest that LIM kinases (LIMKs) promote smooth muscle contraction; however, this has not yet been examined. Here, we studied effects of the LIMK inhibitors on prostate smooth muscle contraction. EXPERIMENTAL APPROACHHuman prostate tissues were obtained from radical prostatectomy. Phosphorylation of cofilin, a LIMK substrate, was examined using a phospho-specific antibody. Smooth muscle contractions were studied in organ bath experiments. KEY RESULTSReal-time PCR, Western blot and immunofluorescence suggested LIMKs are expressed in smooth muscle cells of prostate tissues. Two different LIMK inhibitors, SR7826 (1 μM) and LIMKi3 (1 μM), inhibited contractions of prostate strips, which were induced by electrical field stimulation, α 1 -adrenoceptor agonists phenylephrine and methoxamine and the TXA 2 analogue, U46619. LIMK inhibition in prostate tissues and cultured stromal cells (WPMY-1) was confirmed by cofilin phosphorylation, which was reduced by SR7826 and LIMKi3. In WPMY-1 cells, SR7826 and LIMKi3 caused breakdown of actin filaments and reduced viability. CONCLUSIONS AND IMPLICATIONSSmooth muscle tone in the hyperplastic human prostate may underlie the effects of LIMKs, which promote contraction. Contraction of prostate strips can be inhibited by small molecule LIMK inhibitors.

Inhibition of Prostate Smooth Muscle Contraction by Inhibitors of Polo-Like Kinases

“…This is in line with recent evidence, which suggested that smooth muscle contraction of the human prostate is insufficiently understood. In fact, recent studies reported inhibition of prostate smooth muscle contraction by inhibitors for several kinases or GTPases (including c-Jun N-terminal kinase, focal adhesion kinase, src family kinases, LIM kinases, Rac GTPases) ( Strittmatter et al, 2012 ; Kunit et al, 2014 ; Wang et al, 2016a , b ; Herlemann et al, 2018 ; Yu et al, 2018 ), although their involvement of prostate smooth muscle contraction was not known before. This demonstrates that this process is probably more complex than previously assumed, what may be important from a clinical point of view.…”

Effects of miR-373 Inhibition on Glioblastoma Growth by Reducing Limk1 In Vitro

“…And Limk1 knockdown induced the antitumor effects for lung cancer, breast cancer, or even GBM [ 28 – 30 ]. As an oncogene, it was also evidenced that Limk1 was related to the resistance of chemotherapy [ 48 , 49 ]. Thus, studies on the up- or downstream effector of Limk1 may provide the details of the underlying mechanism on the pathological development of GBM and even the potent novel therapeutic target for the antitumor therapy clinically.…”

Tissue microarray analysis reveals that cofilin expression is a poor prognostic factor in juvenile nasopharyngeal angiofibroma

“…Phosphorylated cofilin is inactive, whereas its activated form is nonphosphorylated. Many studies reported the expression of activated cofilin is significantly increased in ovarian, colorectal, breast, lung, and prostate cancers, whereas the expression of phosphorylated inactive cofilin is significantly decreased. Activated cofilin can induce cancer cells to form invasive pseudopods, determine the direction of cell migration, and promote their proliferation and invasion.…”