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. 2016 Oct;2(10):606-618.
doi: 10.1016/j.trecan.2016.09.001.

The Emerging Role of Cdk5 in Cancer

Free PMC article

The Emerging Role of Cdk5 in Cancer

Karine Pozo et al. Trends Cancer. .
Free PMC article


Cdk5 is an atypical cyclin-dependent kinase that is well characterized for its role in the central nervous system rather than in the cell cycle. However Cdk5 has been recently implicated in the development and progression of a variety of cancers including breast, lung, colon, pancreatic, melanoma, thyroid and brain tumors. This broad pro-tumorigenic role makes Cdk5 a promising drug target for the development of new cancer therapies. Here we review the contribution of Cdk5 to molecular mechanisms that confer upon tumors the ability to grow, proliferate and disseminate to secondary organs, as well as resistance to chemotherapies. We subsequently discuss existing and new strategies for targeting Cdk5 and its downstream mechanisms as anti-cancer treatments.

Keywords: Cdk5; cancer; resistance.


Figure 1 – Key Figure
Figure 1 – Key Figure. Targeting Cdk5 in cancer
(a) Cdk5 contributes to carcinogenesis in several organs throughout the body. (b) Cdk5 activation is dependent on its binding to the cofactor, p35, or its proteolytic cleavage product, p25 (green box). (c) At a cellular level, Cdk5 is involved in the regulation of the cell cycle and cell proliferation by phosphorylating tumor suppressors and transcription factors, and in the DNA damage response upon exposure to genotoxic agents such as chemotherapy and radiotherapy. Cdk5 plays a role in cell motility and migration by regulating the cytoskeleton and focal adhesions. The role of Cdk5 in the DNA damage response and cytoskeleton remodeling has been linked to resistance to common chemotherapies. Therapeutic targeting of Cdk5 is achieved either by 1) inhibiting Cdk5 kinase activity with a pan-Cdk inhibitor or small molecules (d); by 2) preventing Cdk5 binding to p25 using peptides (e); or by 3) interfering with Cdk5 association and phosphorylation of its substrate using peptides (f).
Figure 2
Figure 2. Cdk5-driven mechanisms in cancer progression
(a) Schematic representation of Cdk5 contribution to cell cycle and proliferation. Cdk5 phosphorylates tumor suppressors and transcription factors involved in cell cycle progression. Cyclin I may bind and activate Cdk5 during the cell cycle. The phases at which Cdk5 regulates each transcription factor have not been clearly defined. (b) Proposed role for Cdk5 in the DNA damage response and DNA repair processes. Cdk5 becomes activated in tumor cells exposed to DNA damaging agents (i.e. radiation and chemotherapy). EgR1 induces p35 expression, which binds and activates Cdk5. P35 can be cleaved to produce p25, which activates Cdk5, as in brain cancers. Upon activation, Cdk5 phosphorylates the checkpoint kinase ATM and the transcription factor STAT3 to transduce DNA damage responses and facilitate DNA repair. (c) Cdk5 in cell motility and migration. Cdk5 becomes activated upon stimulation with TGFβ or EGF and phosphorylates components of the cytoskeleton and focal adhesions to induce cell motility and migration. Cdk5 may facilitate neoplasia and angiogenesis through HIF1α and VEGF signaling. Induction of hAsh1 and subsequent expression of p35 may be a mechanism by which Cdk5 is activated as it occurs in lung cancer. The intermediate filament protein, nestin, is a Cdk5 substrate and might regulate the cleavage of p35-to-p25 by an autoregulatory process. (d) Role of Cdk5 in endothelial cell proliferation and migration. Cdk5 is expressed in endothelial cells, is activated by pro-angiogenic factors and regulates angiogenesis by facilitating the migration of endothelial cells via a Rac-dependent mechanism. Abbreviations- Retinoblastoma protein (Rb), E2 transcription factor (E2F), androgen receptor (AR), signal transducer and activator of transcription 3 (STAT3), Cdk5-mediated phosphorylation (P), early growth response protein (EgR1), Ataxia-telangiectasia mutated (ATM), DNA endonuclease (Eme1), human achaete-scute homolog 1 (hASH1), Epithelial-to-mesenchymal transition (EMT), hypoxia-induced factor 1α (HIF1α), Stathmin (Stath), Collapsin Response Mediator Protein-2 (CRMP), focal adhesions (FA), focal adhesion kinase (FAK), Caldesmon (Cald), vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor 1 (VEGFR1).

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