Control of Expression of Key Cell Cycle Enzymes Drives Cell Line-Specific Functions of CDK7 in Human PDAC Cells

Autor:	Lina Kolloch, Teresa Kreinest, Michael Meisterernst, Andrea Oeckinghaus
Rok vydání:	2022
Předmět:	non-covalent CDK7 inhibitor QH301-705.5 pancreatic cancer Gene Expression Regulation Enzymologic Article Catalysis Inorganic Chemistry Cell Line Tumor Biomarkers Tumor Humans Phosphorylation Biology (General) Physical and Theoretical Chemistry Protein Kinase Inhibitors QD1-999 Molecular Biology Spectroscopy Dose-Response Relationship Drug Cell Cycle Organic Chemistry NF-kappa B cyclin-dependent kinase 7/CDK7 General Medicine Cyclin-Dependent Kinases Computer Science Applications Gene Expression Regulation Neoplastic Pancreatic Neoplasms Chemistry Cyclin-Dependent Kinase-Activating Kinase Signal Transduction
Zdroj:	International Journal of Molecular Sciences, Vol 23, Iss 812, p 812 (2022) International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 23; Issue 2; Pages: 812
ISSN:	1422-0067
DOI:	10.3390/ijms23020812
Popis:	Inhibition of the dual function cell cycle and transcription kinase CDK7 is known to affect the viability of cancer cells, but the mechanisms underlying cell line-specific growth control remain poorly understood. Here, we employed a previously developed, highly specific small molecule inhibitor that non-covalently blocks ATP binding to CDK7 (LDC4297) to study the mechanisms underlying cell line-specific growth using a panel of genetically heterogeneous human pancreatic tumor lines as model system. Although LDC4297 diminished both transcription rates and CDK T-loop phosphorylation in a comparable manner, some PDAC lines displayed significantly higher sensitivity than others. We focused our analyses on two well-responsive lines (Mia-Paca2 and Panc89) that, however, showed significant differences in their viability upon extended exposure to limiting LDC4297 concentrations. Biochemical and RNAseq analysis revealed striking differences in gene expression and cell cycle control. Especially the downregulation of a group of cell cycle control genes, among them CDK1/2 and CDC25A/C, correlated well to the observed viability differences in Panc89 versus Mia-Paca2 cells. A parallel downregulation of regulatory pathways supported the hypothesis of a feedforward programmatic effect of CDK7 inhibitors, eventually causing hypersensitivity of PDAC lines.
Databáze:	OpenAIRE
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