Cyclin-Dependent Kinase 5 Activity Controls Cell Motility and Metastatic Potential of Prostate Cancer Cells

Abstract

We show here that cyclin-dependent kinase 5 (CDK5), a known regulator of migration in neuronal development, plays an important role in prostate cancer motility and metastasis. P35, an activator of CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined. Blocking of CDK5 activity with a dominant-negative CDK5 construct, small interfering RNA, or roscovitine resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Expression of a dominant-negative CDK5 in the highly metastatic Dunning AT6.3 prostate cancer cell line also greatly impaired invasive capacity. CDK5 activity was important for spontaneous metastasis in vivo; xenografts of AT6.3 cells expressing dominant-negative CDK5 had less than onefourth the number of lung metastases exhibited by AT6.3 cells expressing the empty vector. These results show that CDK5 activity controls cell motility and metastatic potential in prostate cancer. (Cancer Res 2006; 66(15): 7509-15)

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…Recent studies have uncovered a specific role for Cdk5 in cancer biology and tumor invasiveness [47][48][49] and Cdk5 is highly expressed in a variety of tumors. 47,[50][51][52] These observations suggest that pharmacologic inhibition of Cdk5 activity might optimize outcomes after HCT not only through suppression of T-cell alloreactivity and GVHD, but also through direct antitumor effects.…”

“…An emerging body of data implicate Cdk5 activity in processes and conditions as diverse as neurodegenerative disease, 11,17 inflammation, 13,22,23,31 cancer biology, 47,50-52 and tumor invasiveness. 48,49 Cdk5 was the top hit of 37 genes that when silenced synergistically potentiate effects of proteosome inhibition in myeloma cells, 47 and a cell-based, high-content, screening assay determined that Cdk5 was the biologic target of several cyclin-depending kinase inhibitors that could modulate cancer cell invasion capacity. 48 Cdk5 is highly expressed in a variety of tumors 47,[50][51][52] and several clinical trials studying the use of roscovitine and other nonselective Cdk5 inhibitors in patients with cancer have either been completed or are ongoing.…”

Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population

“…There is presently a substantial amount of data to indicate that CDK5 plays important roles in extraneuronal cells during the process of myogenesis, lens differentiation, spermatogenesis, insulin secretion, apoptosis of ovarian cells and hematopoietic cell differentiation. 3,[5][6][7][8][9][10][11] Furthermore, CDK5 has been suggested to play roles in the regulation of motility of prostate cancer cells, 12 control of glioblastoma cell invasion, 13 modulation of proliferation of medullary thyroid carcinoma cells 14 and apoptotic control of leukemia cells. 15 These potential roles of CDK5 activity in the carcinogenesis of each cell type seem to involve distinct target substrates.…”

Role of CDK5/cyclin complexes in ischemia-induced death and survival of renal tubular cells

“…To confirm these results, we turned our attention to using CDK5 dominant-negative constructions (DNcdk5). 27 DNcdk5 competes with the endogenous CDK5 protein to bind to its activators and substrates. However, DNcdk5 has a point mutation at the catalytic site and is, thus, catalytically inactive.…”

“…However, DNcdk5 has a point mutation at the catalytic site and is, thus, catalytically inactive. 27 LLC-PK1 cells were transfected with either the DNcdk5 construct or a recombinant vector expressing wild-type CDK5 (WtCDK5) as a control and compared with nontransfected cells (Fig. 4).…”