CDK11^p110 plays a critical role in the tumorigenicity of esophageal squamous cell carcinoma cells and is a potential drug target

Abstract

Esophageal squamous cell carcinoma (ESCC) is a serious malignancy with limited options for targeted therapy. The exploration of novel targeted therapies for combating ESCC is urgently needed. Cyclindependent kinases (CDKs) play important roles in the progression of cancers; however, the function of CDK11 p110 (cyclin-dependent kinase 11 p110) in ESCC is still unknown. Here, we investigated the effects and molecular mechanisms of CDK11 p110 in the proliferation and growth of ESCC by examining the expression of CDK11 p110 in ESCC tissues and by detecting phenotypic changes in ESCC cells after CDK11 p110 knockdown or overexpression in vitro and in vivo. According to the tissue microarray analysis, compared with its expression level in normal tissues, the expression level of CDK11 p110 was significantly elevated in ESCC tissues; this result was in concordance with the data in TCGA (The Cancer Genome Atlas) datasets. In addition, RNAi-mediated CDK11 p110 silencing exerted a substantial inhibitory effect on the proliferation, clonogenicity and migration ability of ESCC cells. Further study indicated that CDK11 p110 knockdown arrested ESCC cells in the G2/M phase of the cell cycle and induced cell apoptosis. Moreover, stable shRNA-mediated CDK11 p110 knockdown inhibited tumor growth in an ESCC xenograft model, and overexpression of CDK11 p110 enhanced tumor growth. In addition, the Ki67 proliferation index was closely associated with the elevation or depletion of CDK11 p110 in vivo. In summary, this study provides evidence that CDK11 p110 play a critical role in the tumorigenicity of ESCC cells, which suggests that CDK11 p110 may be a promising therapeutic target in ESCC.

CDK11 Loss Induces Cell Cycle Dysfunction and Death of BRAF and NRAS Melanoma Cells

“…We also observed increased G1-phase cells after CDK11 knockdown, similar to what was reported in breast cancer, another epithelial cancer [13]. In contrast, CDK11 knockdown in esophageal squamous cell carcinoma cells induced G2/M accumulation [56]. CDK11 and Cyclin L1 were recently reported to regulate the cell cycle in non-transformed Bombyx mori (silkworm) cells.…”

The Proteomics and Metabolomics Analysis for Screening the Molecular Targets of Action of β-Eudesmol in Cholangiocarcinoma

“…The CDK11-p110 (known as CDC2L2, CDC2L3, p58GTA, PITSLRE, CDK11-p46, or CDK11-p58) regulates cell proliferation. Downregulation of this protein has been shown to induce cell cycle arrest at G1 phase in human breast cancer cells (Zhou et al, 2015), and at G2/M phase in esophageal squamous cell carcinoma (Du et al, 2019). Moreover, the induction of apoptosis in esophageal squamous cell carcinoma was observed when CDK11-p110 was inhibited by RNA interference (Du et al, 2019).…”

“…Downregulation of this protein has been shown to induce cell cycle arrest at G1 phase in human breast cancer cells (Zhou et al, 2015), and at G2/M phase in esophageal squamous cell carcinoma (Du et al, 2019). Moreover, the induction of apoptosis in esophageal squamous cell carcinoma was observed when CDK11-p110 was inhibited by RNA interference (Du et al, 2019). In the present study, the active form of vitamin B3, nicotinamide (known as niacinamide), was shown to be the metabolite that is linked with the cell cycle.…”

Design, Synthesis, and Biological Evaluation of 2-Anilino-4-Triazolpyrimidine Derivatives as CDK4/HDACs Inhibitors

“…3 The over-expression of CDKs is closely related to the development of tumors. For example, the up-regulation of CDK2, CDK4, CDK6, CDK8, and CDK11 is positively correlated with the occurrence and deterioration of breast cancer, 4 rectal cancer, 5 esophageal cancer, 6 and so on. CDKs have been considered as promising targets for the treatment of cancers.…”