Targeting CDK2 in cancer: challenges and opportunities for therapy

Tadesse, Solomon; Anshabo, Abel Tesfaye; Portman, Neil; Lim, Elgene; Tilley, Wayne D.; Caldon, C. Elizabeth; Wang, Shudong

doi:10.1016/j.drudis.2019.12.001

Cited by 198 publications

(128 citation statements)

References 80 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…CDK2 is a core regulator of cell cycle through late G1-phase and S-phase. CDK2 is thought to be strongly linked to development of cancer, and accumulating evidence shows that inhibition of CDK2 induces cancer cell apoptosis without normal cell damage [ 34 , 35 ]. TOP2A is a marker of proliferation and chemotherapy resistance in cancer [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Explore the Potential Mechanisms of Huangqin-Baishao Herb Pair in Treatment of Cancer

Wang

Liu

2020

Med Sci Monit

View full text Add to dashboard Cite

Background: The aim of this study was to identify the bioactive ingredients of Huangqin-Baishao herb pair and to reveal its anti-cancer mechanisms through a pharmacology approach. Material/Methods: Detailed information on compounds in the HQ-BS herb pair was obtained from the Traditional Chinese medicine systems pharmacology (TCMSP) and screened by the criteria of OB ³30% and DL ³0.18. A systematic drug targeting model (SysDT) was used for compound targets prediction, and then the targets were analyzed for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The protein-protein interaction (PPI) network of HQ-BS targets was constructed, after identifying core networks through Cytoscape plugins. Results: We found 47 bioactive compounds of HQ-BS and 107 human-derived targets. A compound target network and a target signal pathway network were constructed and used for topological analysis. Kaempferol, beta-sitosterol, stigmasterol, wogonin, and oroxylin-a were identified as core compounds and pathways in cancer. The calcium signaling pathway, PI3K-Akt signaling pathway, TNF signaling pathway, chemical carcinogenesis, estrogen signaling pathway, proteoglycans in cancer, HIF-1 signaling pathway, thyroid hormone signaling pathway, VEGF signaling pathway, small cell lung cancer, prostate cancer, colorectal cancer, NOD-like receptor signaling pathway, and T cell receptor signaling pathway were found to be potential signals of HQ-BS in treating cancer. Through PPI network analysis, TNF signaling pathway, tryptophan metabolism, proteoglycans in cancer, cell cycle, and chemical carcinogenesis sub-networks were obtained. Conclusions: HQ-BS contains various bioactive compounds, including flavonoids, phytosterols, and other compounds, and these compounds can inhibit or activate multiple targets and pathways against cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Approach to Explore the Potential Mechanisms of Huangqin-Baishao Herb Pair in Treatment of Cancer

Wang

Liu

2020

Med Sci Monit

View full text Add to dashboard Cite

show abstract

“…We have showed integration of cdk2 activation into platelet signaling and function ex vivo. There is burgeoning interest and development of pharmacologic mediators directed at cdk2 [85][86][87] . The priority accorded cdk2 as a pharmacologic target is timely given the possible role of cdk2 in the diverse physiology of platelets.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase 2 (Cdk2) controls phosphatase-regulated signaling and function in platelets

Woods

Hood

Shiva

et al. 2020

Preprint

View full text Add to dashboard Cite

Cell cycle regulatory molecules including cyclin-dependent kinases can be recruited into non-nuclear pathways to coordinate cell cycling with the energetic state of the cell or with functions such as motility. Little is known about the role of cell cycle regulators in anucleate cells such as platelets. We report that cyclin-dependent kinase (cdk2) is robustly expressed in human platelets, is activated by thrombin and is required for platelet activation. Cdk2 activation required Src signaling downstream of the platelet thrombin receptor PAR1. Kinase-active cdk2 promoted the activation of downstream platelet kinases by phosphorylating and inactivating the catalytic subunit of protein phosphatase 1 (PP1). Erk was bound to PP1 in a complex with the PP1 regulator PPP1R12a (MYPT1) in platelets, and cdk2 inhibited the phosphatase activity of PP1 and PPP1R12a bound complexes. The requirement for cdk2 in Erk activation could be replaced by the phosphatase inhibitor calyculin if cdk2 was inhibited.Blockade of cdk2 kinase with chemical and peptide cdk2 inhibitors resulted in suppression of thrombin-induced platelet aggregation, and partially inhibited GPIIb/IIIa integrin activation as well as platelet secretion of P-Selectin and ATP. Together, these data indicate a requirement for cdk2 in platelet activation.

show abstract

“…Cyclin family plays a pivotal part in cell cycle regulation and is involved in a range of biological processes [30,31]. CDKs, a family of proteins that are involved in the regulation of the cell cycle, are frequently over-expressed or mutated in cancer, and CDK2/4/6 inhibitors (CDK2/4/6i) have been developed to be relatively safe and effective cancer therapeutics [32,33]. From the work presented above, it appears that the CDCA2 may be a crucial functional factor in mitosis and a crucial hub for the regulation of chromatin organization and the maintenance of genome stability.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of CDCA2 in Glioma Predicts Poor Prognosis as Identified by Population-based Analysis

Dong¹,

Liu²

2020

Preprint

View full text Add to dashboard Cite

Background: The cell division cycle-associated protein 2 (CDCA2) was found to be a cell cycle-related protein. CDCA2 was previously reported to be associated with proliferation and migration in multiple cancer. We evaluated the role of CDCA2 in glioma using publicly available data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA).Methods: The relationships between clinical characteristics and CDCA2 expression were analyzed using the Wilcoxon test or Kruskal-Wallis test. Clinicopathologic characteristics associated with overall survival (OS) were analyzed using Cox regression analysis and Kaplan-Meier method. Gene Set Enrichment Analysis (GSEA) was performed to sort the signaling pathway associated with the expression of CDCA2. Pearson correlation test was used to analyse the expression correlation between CDCA2 and well-known cell cycle-related genes.Results: Glioma with high CDCA2 expression was more prone to be associated with advanced malignancy clinical pathologic characteristics and worse prognosis than that with low CDCA2 expression in TCGA and CGGA dataset (P < 0.001). The multiple analysis revealed that CDCA2 was independently associated with OS (HR:1.396; [CI]:1.236 − 1.577, P < 0.001). GSEA showed that cell cycle checkpoint, cell cycle G1/S phase transition, DNA damage checkpoint and regulation of cell cycle arrest were enriched in CDCA2 high expression phenotype. Pearson correlation test revealed that CDCA2 was co-expression with well-known key cell cycle-related genes (CCNA2, CCNB1, CCNB2, CCNE1, CCNE2, CDK1, CDK2, CDK4, CDK6).Conclusion: High CDCA2 expression may be a potential prognosis molecular marker of poor survival in glioma. Cell cycle regulation pathway may be the key pathway regulated by CDCA2 in glioma.

show abstract

Targeting CDK2 in cancer: challenges and opportunities for therapy

Cited by 198 publications

References 80 publications

A Network Pharmacology Approach to Explore the Potential Mechanisms of Huangqin-Baishao Herb Pair in Treatment of Cancer

A Network Pharmacology Approach to Explore the Potential Mechanisms of Huangqin-Baishao Herb Pair in Treatment of Cancer

Cyclin-dependent kinase 2 (Cdk2) controls phosphatase-regulated signaling and function in platelets

Increased Expression of CDCA2 in Glioma Predicts Poor Prognosis as Identified by Population-based Analysis

Contact Info

Product

Resources

About