A role for LIM kinase in cancer invasion

Abstract

In this study, we show that LIM kinase 1 (LIMK1), a critical regulator of actin dynamics, plays a regulatory role in tumor cell invasion. We found that the level and activity of endogenous LIMK1 is increased in invasive breast and prostate cancer cell lines in comparison with less invasive cells. Overexpression of LIMK1 in MCF-7 and in MDA-MB-231 human breast cancer cell lines increased their motility, whereas the specific ROCK and Rho inhibitors Y-27632 and C3, respectively, attenuated this effect. In addition, inhibition of LIMK1 activity in the MDA-MB-231 cells by expression of dominantnegative LIMK1 resulted in decreased motility and formation of osteolytic bone lesions in an animal model of tumor invasion. This study shows an important role for LIMK1 signaling in invasion of cancer, demonstrating its potential as a therapeutic molecular target to decrease metastasis.T umor invasion and metastasis is a critical event for cancer patients as it often results in death. Current therapies are of limited value in most patients with disseminated disease, leaving us with the goal of identifying genes that regulate the metastatic process and designing drugs that target their function. During progression of tumor cells to a metastatic phenotype, they undergo a series of changes that begin with loss of contact inhibition and increased motility, allowing them to migrate from the primary tumor site, invade distant organs, and induce neo-vascularization resulting in metastasis (1). Many of these changes are associated with dynamic actin reorganization and activation of signaling pathways through transmembrane receptors, including receptor tyrosine kinases and phosphatidylinositol 3-kinases (2, 3), G-protein-coupled receptors (4), chemokine receptors (5), and transforming growth factor-␤ receptor (6). In association with cell adhesion molecules at the plasma membrane, the cytoskeleton affects the nature of cell-to-cell and cell-to-substrate interactions via clustered transmembrane integrins that are associated with extracellular matrix proteins (7). These complexes provide the driving force for cell movement and surface remodeling, including neurite extension and axon formation.Members of the small guanosine triphosphatase (GTPase) family control cell adhesion and motility through reorganization of the actin cytoskeleton and regulation of actomyosin contractility (8). We have previously demonstrated the role of the Rho-actomyosin system in tumor cell invasion (9). Both RhoA (10) and the related RhoC (11) are expressed at a relatively higher level in metastatic tumors, and their expression levels positively correlate with the stage of the tumors (12). However, mutations in the Rho gene have not yet been found in human tumors; rather, the overexpression of RhoA in the cell facilitates its translocation from the cytosol to the plasma membrane, where its activation results in stimulation of the actomyosin system, followed by cellular invasion both in vitro and in vivo (13).One of the target molecules of Rho is the family of Rh...

Targeting MRCK and LIMK kinases for cancer therapy

“…1) (5). Results from clinical and basic studies indicate that LIM kinases are important factors in cancer cell invasion and metastasis (5,12), while in vivo studies indicated that interfering with LIMK function inhibited metastasis (13,14). These reports are consistent with the hypothesis that LIMK inhibition would effectively reduce cancer cell invasion and metastasis.…”

Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma

“…Other signals of cellular migration such as the Rho/ROCK pathway and expression of cortactin may be enhanced in such cancer cells. [15][16][17][18] If it were possible to eliminate both signals of cellular migration, then the ability of cancer for invasion might become easier to understand.…”

The cofilin pathway in breast cancer invasion and metastasis

“…In addition, the overexpression of LIMK1 inhibits cell motility in neuroblastoma cell lines 81 and Ras-transformed fibroblasts 82 , whereas dominant-negative LIMK1 increases cell motility in neuroblastoma cell lines 81 . However, the inhibition of LIMK1 expression by siRNA inhibits the motility of Jurkat T cells 51 , and the overexpression of LIMK1 in prostate epithelial cells increases their invasiveness in vitro 83 and the formation of osteolytic lesions in nude mice 84 . Furthermore, a reduction in LIMK1 expression in meta-static prostate cell lines decreases their ability to invade matrigel in vitro 83 .…”