Inhibition of LIM Kinase Inhibits Cancer Growth


The LIM kinase family of serine protein kinases contains two members, LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2). LIMK1 was first isolated from olfactory epithelial cell lines, and LIMK2 from a rat cDNA library using human LIMK1 cDNA as a probe. LIMK1 and 2 are structurally similar and share 50% amino acid homology, human and mouse LIMK1 share 95% amino acid homology. The amino terminus of LIMK contains two double zinc finger LIM domains, followed by a PDZ domain. Both domains are involved in protein-protein interaction. The C-terminus end of the molecule contains the catalytic active kinase domain. LIMK proteins are about 70kDa in size and are expressed in the cytoplasm of most adult and embryonic mouse tissues as well as human tissues. Furthermore, the LIMK1 protein is significantly expressed in highly invasive breast and prostate cancer lineages compared to less invasive cell lines. ADF/cofilin, is a well-known substrate of the LIMK molecule, it acts as an actin depolymerization factor. LIMK interacts with phosphorylate cofilin resulting in inactivation. Cofilin promotes actin depolymerization in the cell by hydrolysing actin filaments (F-actin) and sequestering the monomers (Gactin) from the polymerizing end.

LIMKs are an excellent target point for cancer therapy as they function to regulate the major intracellular network systems of microtubule dynamics and the actin cytoskeleton. Cell growth, invasion and migration were significantly reduced when kinase activity or gene expression of LIMKs were inhibited. Inhibition can be achieved via LIMK specific inhibitor molecules or via gene knockdown techniques, this has been shown in breast and lung cancer cells [11,12]. Recent research outcomes demonstrated that inhibition of LIMK activity blocks tumor progression not only via regulating actin dynamics but also by disrupting mitotic microtubule organization [13-16].

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Nicola B
Editorial Manager
Journal of Biochemistry & Biotechnology