Abstract
Cyclin-dependent kinase 8 (CDK8) has been identified as a colon cancer oncogene. Since this initial observation, CDK8 has been implicated as a potential driver of other cancers including acute myelogenous leukemia (AML) and some breast cancers. Here, we observed different biological responses to CDK8 inhibition among colon cancer cell lines and the triple-negative breast cancer (TNBC) cell line MDA-MB-468. When treated with CDK8 inhibitor 4, all treated cell lines responded with decreased cell viability and increased apoptosis. In the MDA-MB-468 cell line, the decrease in cell viability was dependent on increased phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is not observed in the colon cancer cell lines. Furthermore, increased STAT3 phosphorylation in 4 treated MDA-MB-468 cells was dependent on increased transcription factor E2F1 protein. These results are consistent with previous reports of exogenous expression of E2F1-induced apoptosis in MDA-MB-468 cells.
Highlights
Cyclin-dependent kinase 8 (CDK8) is a positive regulator of the cell cycle and has been described as an oncogene in the context of chromosomal amplification in colon cancer cell lines [1,2]
Since the initial suggestion that CDK8 is an oncogene relevant to colon cancer and may play a role in other types of tumors including breast tumors, we attempted to compare the effects of CDK8 inhibitor 4 on colon cancer cell lines and the triple-negative breast cancer (TNBC) cell line MDA-MB-468
It is interesting to note that CDK8 is amplified in a significant number of breast cancers, but low β–catenin levels are correlated with poor prognosis [22]
Summary
Cyclin-dependent kinase 8 (CDK8) is a positive regulator of the cell cycle and has been described as an oncogene in the context of chromosomal amplification in colon cancer cell lines [1,2]. Amplification of 13q12 occurs in a significant fraction of colon cancer and CDK8 was identified by an RNA interference screen as a relevant gene target and likely oncogene. Knockdown of CDK8 in colon cancer cell lines led to decreased proliferation. CDK8 was shown to regulate the β–catenin transcriptional activity. Due to the role of many CDK family members in the regulation of the cell cycle or regulation of transcription, these proteins have become of interest as potential drug targets of cancer therapeutics [3,4]
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