Tumorigenesis is a series of complex processes, with a variety of aberrant signaling changes which confer cells cancerous characteristics. Surgery therapy is no more the only way for cancer treatment, looking for the potential biomarkers and effective target therapies has become the current hotspot [
63]. The emerging knowledge of the roles of Cdk5 in cancer indicates that it is a potential biomarker for diagnosis and prognosis prediction for cancer. Cdk5 is reported to be over-expressed or hyperactivated in various cancer tissues and tumor cell lines. In patients with lung cancer it is associated with clinical pathological characteristics and poorer prognoses [
64]. In head and neck squamous cell carcinoma, aberrant over-expression of Cdk5 significantly induces tumor cell motility and epithelial mesenchymal transition (EMT), which is considered as a pivotal process of cancer metastasis [
65]. In hepatocelluar carcinoma (HCC), over-expression and hyperactivation of Cdk5 play an oncogenic activity by inducing proliferation and clonogenic growth of HCC [
66]. In pancreatic cancer cells, Cdk5 is widely active. Blockade of Cdk5 can remarkably downregulate the two active forms of Ral proteins RalA-GTP and RalB-GTP, and Rho-GTP and Rac-GTP levels, all of which play an important role in oncogenic Ras-induced neoplasia, tumor progression and metastasis, revealing the important roles of Cdk5 in cancer progression [
67]. The roles of Cdk5 in pancreatic cancer formation and progression via Ras-Ral signaling have been further proven by rescue test, in which constitutively activating RalA-GTP and RalB-GTP in pancreatic cancer cells expressing dominant-negative Cdk5 significantly rescued the effects of Cdk5 inhibition [
67]. In prostate cancer cells, Cdk5 promotes cell growth in an androgen receptor (AR)- independent way and maintains high AKT kinase activity, which is known to correlate with prostate cancer progression and considered as a critical growth-promoting pathway in prostate cancer cells [
68]. There are also reports that Cdk5 mediates prostate cancer progression through STAT3 and AR signaling [
69]. In breast cancer cells treated with transforming growth factor beta 1 (TGF-β1, an EMT inducer), both p35 and Cdk5 are up-regulated and hyperactivated, leading to subsequent EMT and cancer cell motility by phosphorylating Fak, which is known to be involved in cellular adhesion and spreading processes [
70]. Our work also shows Cdk5 and p35 are significantly increased in clinical breast cancer tissues and in breast cancer cell lines exposed to paclitaxel at transcriptional and translational levels.
Though Cdk5 is generally up-regulated in most types of cancer, it has also been reported down-regulated in certain types of cancer. For example, in human gastric cancer tissues, the mRNA level and protein level of Cdk5 and p35 are both significantly reduced, and the down-regulation is linked with poorer prognoses [
71]. Cellular experiments show a lack of Cdk5 in nucleus in different gastric cancer cell lines, but presence of Cdk5 in both the nucleus and cytoplasm in normal gastric epithelial cell line. NS-0011, which inhibits the translocation of Cdk5 from nucleus to cytoplasm, can suppress the proliferation and xenograft tumorigenesis of gastric cancer cells [
71]. The effects of disrupting the localization of Cdk5 by drugs reveal a novel mechanism to limit its pathological signalings in cancer cells [
71].
Taken all together, Cdk5 participates in tumorigenesis, progression and metastasis of different cancers through various signaling pathways, and its inhibition and knockdown have been proven to be effective in restraining cancer cell progression. All the studies provide potential targets of Cdk5-relating pathways for cancer treatment.