title: 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.affiliation: Senex Biotechnology, Inc., Columbia, SC 29208, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Porter
authors.forename: Elena
authors.initials: E
authors.lastname: Farmaki
authors.forename: Serena
authors.initials: S
authors.lastname: Altilia
authors.forename: Gary P
authors.initials: GP
authors.lastname: Schools
authors.forename: Deborah K
authors.initials: DK
authors.lastname: West
authors.forename: Mengqian
authors.initials: M
authors.lastname: Chen
authors.forename: Bey-Dih
authors.initials: BD
authors.lastname: Chang
authors.forename: Anatoliy T
authors.initials: AT
authors.lastname: Puzyrev
authors.forename: Chang-uk
authors.initials: CU
authors.lastname: Lim
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rokow-Kittell
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Friedhoff
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
authors.forename: Swathi
authors.initials: S
authors.lastname: Kalurupalle
authors.forename: Gregory
authors.initials: G
authors.lastname: Hurteau
authors.forename: Jun
authors.initials: J
authors.lastname: Shi
authors.forename: Phil S
authors.initials: PS
authors.lastname: Baran
authors.forename: Balazs
authors.initials: B
authors.lastname: Gyorffy
authors.forename: Mark P
authors.initials: MP
authors.lastname: Wentland
authors.forename: Eugenia V
authors.initials: EV
authors.lastname: Broude
authors.forename: Hippokratis
authors.initials: H
authors.lastname: Kiaris
authors.forename: Igor B
authors.initials: IB
authors.lastname: Roninson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D016922:Cellular Senescence; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; D056850:Cyclin-Dependent Kinase 8