LIMK1 and LIMK2 Are Important for Metastatic Behavior and Tumor Cell-Induced Angiogenesis of Pancreatic Cancer Cells

Abstract

The two LIM kinases (LIMKs) LIMK1 and LIMK2 are members of the PDZ/LIM family. These serine/threonine protein kinases are involved in actin cytoskeleton reorganization through phosphorylation and inactivation of ADF/cofilin. Different subcellular localizations of LIMK1 and LIMK2 suggest different functions. LIMK1 is implicated in microtubule disassembly in endothelial- and cancer cells, whereas LIMK2 plays a role in cell cycle progression. To compare the role of the two LIMKs in cancer-related processes, we used a cell-based in vitro migration assay, as well as two zebrafish xenograft assays. We analyzed here the metastatic behavior and tumor cell-induced neovascularization of pancreatic cancer cells in which both LIMK genes were silenced by siRNAs. Both LIMK1 and LIMK2 single knock down led to a reduction of invasion and metastatic behavior in the zebrafish xenograft metastasis assay. Interestingly, the double knock down completely blocked invasion and formation of micrometastasis in vivo. Moreover, in the zebrafish xenograft angiogenesis assay, we observed a reduction of pancreatic cancer cell-induced angiogenesis for both the LIMK1 and LIMK2 knockdowns. Our results demonstrate similar functions for the two LIMKs in pancreatic cancer cells and suggest an important role for both LIMK1 and LIMK2 in tumor progression and metastasis formation.