Cyclin Dependent Kinase (CDK) An alternative treatment could be targeting and inhibiting the atypical cyclin-dependent kinase CDK5. CDKs regulate the progression of cells through the cell cycle, and cancer proliferation relies on deregulation of this cycle. Previously, CDK5 has been solely recognised for its action in the central nervous system (Dhavan and Tsai, 2001), but has more recently become a molecule of interest in various cancer therapies, due to its pro-tumorigenic role and function in the progression of cancers (Pozo and Bibb, 2016). One said function being its role in angiogenesis.
The control of activity of CDK5 is unlike any other CDK (Cicenas et al, 2015). CDK5 is activated by p35 or p39, non-cyclin activators, or its proteolytic cleavage product p25. It phosphorylates substrates on serine or threonine residues and tumour suppressors and transcription factors. It is also involved in DNA damage when exposed to chemotherapy and radiotherapy. Resistance to common chemotherapies has been linked to its ability to remodel the cytoskeleton and cause DNA damage. There are various forms of activated CDK5 including: CDK5/cyclin I complex; CDK5/p35; CDK5/p39; CDK5/p25; and CDK5/p29 which all have various actions in cancer.
There are a few current strategies for targeting CDK5, these include: small molecule inhibitors; disruption of CDK5/activator binding using a peptide; targeting CDK5/substrate interaction through small interfering peptides and drug combinations. One of the small molecule inhibitors widely used in cell lines and mouse models is Roscovitine, a purine analogue. The analogue inhibits CDK 1, 2, 9 and 7 (Cicenas et al., 2015) but had no effects on CDK 4/6, making it an effective tool to study. However, Roscovitine’s use in clinical trials has been inconclusive.
Herzog et al.,(2016) investigated the relationship between CDK5 and HIF to determine the benefits of using CDK5 targeting as a therapy option in Hepatocellular Carcinoma (HCC). In HCC, CDK5 is highly expressed, promoting metastasis, and the progression and invasion of tumours.
These solid tumours are highly vascularised and show increased VEGF, which directly corresponds with poorer survival of patients overall. The investigation highlighted that in endothelial and liver cancer cells, CDK5 stabilises HIF-1? through phosphorylation at serine 687, proving that CDK5 is a viable new target for reducing vascularisation in tumours. As a potential link between CDK5 and HIF-1? was previously hypothesised, the study examined the effect of inhibition or overexpression of HIF-1? by CDK5. Inhibition of CDK5 pharmacologically, by roscovitine, along with genetic down-regulation of CDK5, decreased the protein level of HIF-1?. The increased level of VEGFA and VEGFRI, induced by hypoxia, was reduced by pharmacological CDK5 inhibition and with siRNA mediated down regulation. Since CDK5 has been long overlooked, much research is still to be done regarding its use clinically.
However recent studies show that CDK5 appears to be central to tumorigenic pathways making it a valid target for anti-cancer drugs in the future. An effective strategy may be to target downstream pathways in addition to CDK5.