Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread—Identification of a Promising Novel therapeutic target

Abstract

Despite considerable progress in recent years, the overall prognosis of metastatic malignant melanoma remains poor, and curative therapeutic options are lacking. Therefore, better understanding of molecular mechanisms underlying melanoma progression and metastasis, as well as identification of novel therapeutic targets that allow inhibition of metastatic spread, are urgently required. The current study provides evidence for aberrant cyclin-dependent kinase 5 (CDK5) activation in primary and metastatic melanoma lesions by overexpression of its activator protein CDK5R1/p35. Moreover, using melanoma in vitro model systems, shRNA-mediated inducible knockdown of CDK5 was found to cause marked inhibition of cell motility, invasiveness, and anchorage-independent growth, while at the same time net cell growth was not affected. In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases. Inhibition of lung metastasis was further validated in a syngenic murine melanoma model. CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype. Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells. Thus, experimental data presented here provide strong evidence for a crucial role of aberrantly activated CDK5 in melanoma progression and metastasis and establish CDK5 as promising target for therapeutic intervention.

The Emerging Role of Cdk5 in Cancer

“…Cdk5 activity drives the migration and metastatic invasion of some forms of lung [42], prostate [29, 43], pancreas [6, 44], melanoma [45], pituitary [13] and thyroid [27] cancers. The migration of these cancer cells in culture or in vivo is stopped upon Cdk5 inhibition (Figure 2c).…”

“…Cdk5 regulates the formation of F-actin bundles in breast cancer cells [15]. Furthermore, Cdk5 modifies actin dynamics regulators such as caldesmon, an actin- and calmodulin-binding protein that participates in the migration and metastatic invasion of melanoma and breast cancer cells [45]. Cdk5 has long been implicated in the regulation of microtubule complexes that are essential for cell motility.…”

“…Thus targeting Cdk5 along with Cdk1, 2, 9 may be a valid anti-cancer strategy. Other small molecule inhibitors CP681301 [55], indolinone A [56] and PJB [45] exhibit increased selectivity for Cdk5 and Cdk2 over other Cdks and anti-cancer activity in cell lines [12, 45], but in vivo preclinical studies remain to be conducted. Thus more inhibitors are available to target Cdk5 more specifically.…”

MicroRNA 143‐5p regulates alpaca melanocyte migration, proliferation and melanogenesis

“…Cellular miRNA levels are tightly controlled through the process of maturation, which consequently affects target recognition . There is a growing number of identified miRNAs that regulate molecular pathways involved in melanocyte biology by targeting the relevant genes .…”

Biological functions of CDK5 and potential CDK5 targeted clinical treatments

“…Additionally, knockdown of CDK5 in melanoma cell lines decreased cell motility and cell spreading in vitro , and decreased formation of lung and liver metastases in vivo in a mouse model of human melanoma. The decrease in CDK5 expression led to decreased phosphorylation of caldesmon, which decreased its binding affinity with actin and calmodulin (Figure 2) [49]. Another mechanism by which CDK5 may promote cell migration is by enhancing pro-migratory P13K/AKT signaling.…”