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.transcriptional damage response | senescence | tumor microenvironment | nucleolus | chemical genomics

CDK8/19 Mediator kinases potentiate induction of transcription by NFκB

“…Several groups are currently in the process of developing CDK8/19 inhibitors for cancer therapy applications (18). Although a recent paper reported significant toxicity of two CDK8/19-inhibiting small molecules (19), no toxicity has been reported in animal studies with other CDK8/19 inhibitors, including those used in the present work (3,8,16,17).…”

“…CDK8/19 regulation is especially pertinent in cancers, where CDK8 positively regulates several cancer-relevant signaling pathways (5), including Wnt/β-catenin (9), the serum response network (6), TGFβ (10), HIF1α (7), and estrogen receptor (8). CDK8 has been identified as an oncogene implicated in colorectal (9), pancreatic (11), and breast (3,8,12,13) cancers and melanomas (14) and associated with the stem cell phenotype (15). CDK8/19 inhibition also has an antiproliferative effect in a subset of leukemias (16,17).…”

“…The effect of CDK8/19 inhibitors against the induction of NFκB-mediated transcription by p21 has been linked to the ability of p21 to bind CDK8 and stimulate its kinase activity (3). However, CDK8 is also active in the absence of p21, and thus we were interested in exploring whether CDK8/19 inhibition would affect the induction of NFκB transcriptional activity by a p21-independent canonical pathway.…”

“…NFκB has been identified as a key factor mediating the induction of transcription of tumor-promoting cytokines and other disease-associated genes by chemotherapy-induced DNA damage (3) or by the damage-inducible cell cycle inhibitor p21 (CDKN1A) (4). Using chemical genomics, we have developed a series of small molecules that suppress the induction of transcription by p21 or by DNA damage; the activities of these compounds include suppression of the induction of an NFκB-dependent consensus promoter by p21.…”

“…Using chemical genomics, we have developed a series of small molecules that suppress the induction of transcription by p21 or by DNA damage; the activities of these compounds include suppression of the induction of an NFκB-dependent consensus promoter by p21. These compounds were identified as selective inhibitors of two closely related cyclindependent kinases (CDKs), CDK8 and CDK19 (3). CDK8 (universally expressed) and its closely related paralog CDK19 (variably expressed) are alternative subunits of the regulatory CDK module of the transcriptional Mediator complex.…”