Abstract
LIM kinases (LIMKs) are important cell cytoskeleton regulators that play a prominent role in cancer manifestation and neuronal diseases. The LIMK family consists of two homologues, LIMK1 and LIMK2, which differ from one another in expression profile, intercellular localization, and function. The main substrate of LIMK is cofilin, a member of the actin-depolymerizing factor (ADF) protein family. When phosphorylated by LIMK, cofilin is inactive. LIMKs play a contributory role in several neurodevelopmental disorders and in cancer growth and metastasis. We recently reported the development and validation of a novel LIMK inhibitor, referred to here as T56-LIMKi, using a combination of computational methods and classical biochemistry techniques. Here we report that T56-LIMKi inhibits LIMK2 with high specificity, and shows little or no cross-reactivity with LIMK1. We found that T56-LIMKi decreases phosphorylated cofilin (p-cofilin) levels and thus inhibits growth of several cancerous cell lines, including those of pancreatic cancer, glioma and schwannoma. Because the most promising in-vitro effect of T56-LIMKi was observed in the pancreatic cancer cell line Panc-1, we tested the inhibitor on a nude mouse Panc-1 xenograft model. T56-LIMKi reduced tumor size and p-cofilin levels in the Panc-1 tumors, leading us to propose T56-LIMKi as a candidate drug for cancer therapy.
Highlights
LIM kinases (LIMK) and cofilinLIM kinase 1 and 2 (LIMK1/2) are key regulators of the actin cytoskeleton
We found that the cells transfected with HA-LIMK1 or HA-LIMK2 expressed the corresponding enzymes (Fig. 1 A and B)
We recently reported the development of a new LIMK inhibitor, T56-LIMKi, that inhibited cofilin phosphorylation, cell growth and migration, and colony formation of NF1-depleted mouse embryonic fibroblasts (MEFs) in soft agar [36]
Summary
LIM kinases (LIMK) and cofilinLIM kinase 1 and 2 (LIMK1/2) are key regulators of the actin cytoskeleton. They are dual-specificity kinases, phosphorylating both serine/threonine and tyrosine residues [6, 7] Both are ubiquitous and are expressed in various tissues [8, 9]. They share 50% homology in amino-acid sequence, with higher conservation in specific domains (e.g. 70% sequence homology in the kinase domain). Their expression patterns, are different: LIMK1 is expressed mainly in embryonic brain tissue and heart [9], whereas LIMK2 is expressed in all tissues [8]. They have different subcellular localizations: whereas LIMK1 is mainly localized to the focal adhesion site, LIMK2 is found throughout the cytoplasm and in association with the cis-Golgi compartment [7, 10]
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