A review on the role of cyclin dependent kinases in cancers

Abstract

The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.

Keywords: CDK; Cancer; Cyclin dependent kinases.

Fig. 1

A schematic diagram of CDK1 and the role of WTAP in modulating CDK2 in renal cell carcinoma. Mounting evidence has demonstrated the roles of N6-methyladenosine (m6A) in physiological processes and the progression of various human cancers such as cell cycle regulation that is mostly dependent on cyclins and CDKs. As a component in the m6A ‘writers’, WTAP is detected to be an RNA-binding protein and has a role in the m6A modification, mRNA splicing as well as processing. As an illustration, a recent study has detected that WTAP, an important component of the m6A writer complex, could have an oncogenic role in renal cell carcinoma tumorigenesis via physically binding to CDK2 transcript and promoting its transcript stability [68]

Fig. 2

A schematic illustration of the role of STAT3 signaling cascade in regulating CDK1 and CDK2 in lung cancer. Accumulating evidence has illustrated that CDK1/GP130/STAT3 signaling could promote lung cancer tumorigenesis. It has been reported that Iron-dependent CDK1 activity could phosphorylate 4E-BP1, which in turn elevates STAT3 signaling pathway via upregulation of GP130 [48]. Moreover, another research has revealed that PROS could downregulate VEGF induced proliferation, migration, and tube formation in non-small lung cancer cells and inhibits angiogenesis in chorioallantoic membrane assay through attenuating phosphorylation of VEGFR2, Src, and STAT3, thereby inducing sub G1 accumulation, S phase arrest [158]

Fig. 3

A schematic representation of the role of PI3K/AKT/mTOR and MAPK/ERK signaling pathways in regulating the expression of CDK2 and CDK4/6 in various human cancers