Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities.

Abstract

Conventional chemotherapy not only kills tumor cells but also changes gene expression in treatment-damaged tissues, inducing production of multiple tumor-supporting secreted factors. This secretory phenotype was found here to be mediated in part by a damage-inducible cell-cycle inhibitor p21 (CDKN1A). We developed small-molecule compounds that inhibit damage-induced transcription downstream of p21. These compounds were identified as selective inhibitors of a transcription-regulating kinase CDK8 and its isoform CDK19. Remarkably, p21 was found to bind to CDK8 and stimulate its kinase activity. p21 and CDK8 also cooperate in the formation of internucleolar bodies, where both proteins accumulate. A CDK8 inhibitor suppresses damage-induced tumor-promoting paracrine activities of tumor cells and normal fibroblasts and reverses the increase in tumor engraftment and serum mitogenic activity in mice pretreated with a chemotherapeutic drug. The inhibitor also increases the efficacy of chemotherapy against xenografts formed by tumor cell/fibroblast mixtures. Microarray data analysis revealed striking correlations between CDK8 expression and poor survival in breast and ovarian cancers. CDK8 inhibition offers a promising approach to increasing the efficacy of cancer chemotherapy.

• Authors: Donald C Porter, Elena Farmaki, Serena Altilia, Gary P Schools, Deborah K West, Mengqian Chen, Bey-Dih Chang, Anatoliy T Puzyrev, Chang-uk Lim, Rebecca Rokow-Kittell, Lawrence T Friedhoff, Athanasios G Papavassiliou, Swathi Kalurupalle, Gregory Hurteau, Jun Shi, Phil S Baran, Balazs Gyorffy, Mark P Wentland, Eugenia V Broude, Hippokratis Kiaris, Igor B Roninson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 34 Pg. 13799-804 (Aug 21 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22869755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Cyclin-Dependent Kinase Inhibitor p21
• S-Phase Kinase-Associated Proteins
• SKP1 protein, human
• Cyclin-Dependent Kinase 8

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Nucleolus (metabolism)
• Cellular Senescence
• Cyclin-Dependent Kinase 8 (metabolism, physiology)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Gene Expression Regulation, Neoplastic
• Genomics
• Humans
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• Neoplasms (drug therapy, metabolism)
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic
• S-Phase Kinase-Associated Proteins (metabolism)
• Transcription, Genetic
• Treatment Outcome