Cyclin-dependent kinase 5 regulates the proliferation, motility and invasiveness of lung cancer cells through its effects on cytoskeletal remodeling

Abstract

Abstract. Determining the molecular phenotype is a key to understanding and predicting the metastatic potential and the prognosis for patients with lung cancer. Our previous study demonstrated that increased expression of cyclin-dependent kinase 5 (CDK5) in patients with non-small cell lung cancer (NSCLC) is associated with a poorer prognosis. The present study aimed to further investigate the underlying mechanism of CDK5 in vitro and in vivo using the A549 human NSCLC cell line. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to quantify the proliferation of the A549 cells; migration assay and invasiveness assays were performed using Transwell chambers and wound healing assays were used to assess cell motility, which was assessed by measuring the movement of cells. Inhibition of CDK5 by roscovitine and small interfering (si)RNA was used to investigate the mechanism of CDK5 in the process of A549 lung cancer cell proliferation, migration and invasion. The results demonstrated that functional inhibition of CDK5 using roscovitine and siRNA markedly suppressed the proliferation of A549 cells and resulted in a reduced tumor mass in vivo. In addition, the hinhibition of CDK5 reduced the migration and invasiveness of the A549 cells in vitro and in vivo. Notably, CDK5 inhibition also impaired tumor cell cytoskeletal remodeling and led to loss of cell polarity, which may partially explain the reduction of A549 cell mobility and invasiveness.The results of the present study revealed that CDK5 may be important in the regulation of migration and invasiveness in NSCLC through its effects on cytoskeletal remodeling. IntroductionLung cancer has long been the leading cause of cancer-associated mortality worldwide (1). Although numerous therapeutic strategies have improved significantly, the presence of locally advanced or metastatic lung cancer reduces the curability of this life-threatening disease. Several efforts have been made to understand the mechanism and molecular pathogenesis of this disease, with promise in the development of more effective targeted treatment strategies for lung cancer, particularly non-small cell lung cancer (NSCLC). Certain small molecular inhibitors have been developed against certain tyrosine kinases, including epidermal growth factor receptor and vascular endothelial growth factor receptor (2); however, the overall progression free survival rate has not improved satisfactorily (3). The poor survival rate is predominantly attributed to aggressive growth, advanced stage at diagnosis and local recurrence (4). The identification of effectors, which modulate growth, cell migration and invasion will assist in understanding the process of disease progression and enable the development of novel therapeutic targets for patients with NSCLC.Cyclin-dependent kinase 5 (CDK5) has been recognized as a key factor in regulating the migration and plasticity of neuron cells (5,6). Compared with other CDKs, CDK5 is considered to be an essential regulator of neuronal differentiation, ra...

Clinical role and biological function of CDK5 in hepatocellular carcinoma: A study based on immunohistochemistry, RNA-seq andin vitroinvestigation

“…Similarly, Liu JL. Et al.’s study on CDK5 and lung cancer revealed a similar CDK5 proliferation and apoptosis trend in lung cancer cell lines when CDK5 activity was suppressed by siRNA [ 29 ]. A paradoxical mechanism of CDK5 in HCC was previously reported.…”

The Emerging Role of Cdk5 in Cancer

“…Cdk5 has indeed been implicated in resistance to PARP inhibitors [16, 32, 34, 39], topoisomerase inhibitors and DNA crosslinkers. In line with these observations, treatment of the NSCLC cell line, A549, the proliferation of which is driven by Cdk5 [11], with the Cdk5 inhibitor, roscovitine, enhanced its sensitivity to IR [40]. In all cases, Cdk5 inhibition or Cdk5 knock-down restored chemotherapeutics sensitivity.…”

“…Second, mRNA and protein expression levels of Cdk5 and its activators are increased, or decreased, in several forms of cancer and these alterations are correlated with cancer severity (Figure 1a, Key Figure; Table 1). For example, Cdk5 and p35/p25 are elevated in pulmonary neuroendocrine cancers [9–11], in sporadic and familial forms of medullary thyroid carcinoma (MTC) [12] and pituitary adenoma [13]. In fact Cdk5 and p35/p25 expression appear to typify neuroendocrine cancer pathology.…”

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

“…Interestingly, CDK5 activity is required for cell invasion in prostate carcinoma, glioblastoma multiforme [2], pancreatic cancer [3], medullary thyroid cancer [4]. Inhibition of CDK5 activity decreases lung cancer cell motility [5]. Liu et al have also reported that increased CDK5 expression in patients with non-small cell lung cancer is correlated with poor prognosis [6].…”