Downregulation of p57^kip2 promotes cell invasion via LIMK/cofilin pathway in human nasopharyngeal carcinoma cells

Abstract

The members of Rho family are well known for their regulation of actin cytoskeleton to control cell migration. The Cip/kip members of cyclin-dependent (CDK) inhibitors have shown to implicate in cell migration and cytoskeletal dynamics. p57(kip2) , a CDK inhibitor, is frequently down-regulated in several malignancy tumors. However, its biological roles in human nasopharyngeal carcinoma (NPC) cells remained to be investigated. Here, we found p57(kip2) has nuclear and cytoplasm distributions and depletion of endogenous p57(kip2) did not change the cell-cycle progression. Inhibition of cell proliferation by mitomycin C promoted FBS-mediated cell migration and accompanied with the downregulation of ΔNp63α and p57(kip2), but did not change the level of p27(kip1) , another CDK inhibitor. By using siRNA transfection and cell migration/invasion assays, we found that knockdown of p57(kip2) , but not ΔNp63α, involved in promotion of NPC cell migration and invasion via decrease of phospho-cofilin (p-cofilin). Treatment with Y-27632, a specific ROCK inhibitor, we found that dysregulation of ROCK/cofilin pathway decreased p-cofilin expression and induced cell migration. This change of p-cofilin induced actin remodeling and pronounced increase of membrane protrusions. Further, silence of p57(kip2) not only decreased the interaction between p57(kip2) and LIMK-1 assayed by immunoprecipitation but also reduced the level of phospho-LIMK1/2. Therefore, this study indicated that dysregulation of p57(kip2) promoted cell migration and invasion through modulation of LIMK/cofilin signaling and suggested this induction of inappropriate cell motility might contribute to promoting tumor cell for metastasis.

Leptin Activates RhoA/ROCK Pathway to Induce Cytoskeleton Remodeling in Nucleus Pulposus Cells

“…Previous studies have shown that actin cytoskeleton rearrangement induced by ROCK activation requires a cyclic activation and inactivation of cofilin, which is regulated by LIMK-dependent phosphorylation [22]. Our data indicates that leptin rapidly activates Rho GTPases, leading to LIMK1 and cofilin phosphorylation.…”

Integrin-binding Protein Nischarin Interacts with Tumor Suppressor Liver Kinase B1 (LKB1) to Regulate Cell Migration of Breast Epithelial Cells

“…LIMK1 is highly expressed in invasive breast cancer cell lines and invasive tumors (7), suggesting a pro-tumorigenic function of LIMK. In support of this, the LIMK pathway has been shown to have a major role in cell migration and invasion (8), as well as tumor growth and metastasis (7). This study, for the first time, shows that LKB1 inhibits LIMK phosphorylation to regulate cofilin functions.…”

“…p21-activated kinase (PAK), 2 a downstream effector of Rac and Cdc42, is linked to cancer. High expression of PAK is detected in several breast tumor types, and activation of PAK leads to increased DNA synthesis, cell proliferation, anchorage-independent growth (7), and tumor growth (8). Moreover, PAKs phosphorylate and activate LIM kinase (LIMK), leading to increased phosphorylation of cofilin, which is important in regulating actin turnover.…”

Targeting Cdk11 in osteosarcoma cells using the CRISPR‐cas9 system

“…Recent studies have shown that CDKs and their cyclin family are important for cell migration in several types of tumors. [26][27][28][29] However, direct evidence demonstrating the relationship between expression of CDK11 and migration and invasion of cancer cells is lacking. We assessed whether knockout of CDK11 by CRISPR-Cas9 transfection could affect the migratory activity of osteosarcoma cells using a wound healing assay.…”