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

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, B. Györffy, Mark P. Wentland, Eugenia V. Broude, Hippokratis KiarisIgor B. Roninson

Research output: Contribution to journalArticle

75 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13799-13804
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number34
DOIs
Publication statusPublished - Aug 21 2012

Fingerprint

Cyclin-Dependent Kinase 8
Drug Therapy
Neoplasms
Phosphotransferases
Fibroblasts
Microarray Analysis
Heterografts
Ovarian Neoplasms
Cell Cycle
Protein Isoforms
Breast Neoplasms

Keywords

  • Chemical genomics
  • Nucleolus
  • Senescence
  • Transcriptional damage response
  • Tumor microenvironment

ASJC Scopus subject areas

  • General

Cite this

Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. / Porter, Donald C.; Farmaki, Elena; Altilia, Serena; Schools, Gary P.; West, Deborah K.; Chen, Mengqian; Chang, Bey Dih; Puzyrev, Anatoliy T.; Lim, Chang Uk; Rokow-Kittell, Rebecca; Friedhoff, Lawrence T.; Papavassiliou, Athanasios G.; Kalurupalle, Swathi; Hurteau, Gregory; Shi, Jun; Baran, Phil S.; Györffy, B.; Wentland, Mark P.; Broude, Eugenia V.; Kiaris, Hippokratis; Roninson, Igor B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 34, 21.08.2012, p. 13799-13804.

Research output: Contribution to journalArticle

Porter, DC, Farmaki, E, Altilia, S, Schools, GP, West, DK, Chen, M, Chang, BD, Puzyrev, AT, Lim, CU, Rokow-Kittell, R, Friedhoff, LT, Papavassiliou, AG, Kalurupalle, S, Hurteau, G, Shi, J, Baran, PS, Györffy, B, Wentland, MP, Broude, EV, Kiaris, H & Roninson, IB 2012, 'Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 34, pp. 13799-13804. https://doi.org/10.1073/pnas.1206906109
Porter, Donald C. ; Farmaki, Elena ; Altilia, Serena ; Schools, Gary P. ; West, Deborah K. ; Chen, Mengqian ; Chang, Bey Dih ; Puzyrev, Anatoliy T. ; Lim, Chang Uk ; Rokow-Kittell, Rebecca ; Friedhoff, Lawrence T. ; Papavassiliou, Athanasios G. ; Kalurupalle, Swathi ; Hurteau, Gregory ; Shi, Jun ; Baran, Phil S. ; Györffy, B. ; Wentland, Mark P. ; Broude, Eugenia V. ; Kiaris, Hippokratis ; Roninson, Igor B. / Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 34. pp. 13799-13804.
@article{4c604da0212647fa86248881ee465308,
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.",
keywords = "Chemical genomics, Nucleolus, Senescence, Transcriptional damage response, Tumor microenvironment",
author = "Porter, {Donald C.} and Elena Farmaki and Serena Altilia and Schools, {Gary P.} and West, {Deborah K.} and Mengqian Chen and Chang, {Bey Dih} and Puzyrev, {Anatoliy T.} and Lim, {Chang Uk} and Rebecca Rokow-Kittell and Friedhoff, {Lawrence T.} and Papavassiliou, {Athanasios G.} and Swathi Kalurupalle and Gregory Hurteau and Jun Shi and Baran, {Phil S.} and B. Gy{\"o}rffy and Wentland, {Mark P.} and Broude, {Eugenia V.} and Hippokratis Kiaris and Roninson, {Igor B.}",
year = "2012",
month = "8",
day = "21",
doi = "10.1073/pnas.1206906109",
language = "English",
volume = "109",
pages = "13799--13804",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "34",

}

TY - JOUR

T1 - Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities

AU - Porter, Donald C.

AU - Farmaki, Elena

AU - Altilia, Serena

AU - Schools, Gary P.

AU - West, Deborah K.

AU - Chen, Mengqian

AU - Chang, Bey Dih

AU - Puzyrev, Anatoliy T.

AU - Lim, Chang Uk

AU - Rokow-Kittell, Rebecca

AU - Friedhoff, Lawrence T.

AU - Papavassiliou, Athanasios G.

AU - Kalurupalle, Swathi

AU - Hurteau, Gregory

AU - Shi, Jun

AU - Baran, Phil S.

AU - Györffy, B.

AU - Wentland, Mark P.

AU - Broude, Eugenia V.

AU - Kiaris, Hippokratis

AU - Roninson, Igor B.

PY - 2012/8/21

Y1 - 2012/8/21

N2 - 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.

AB - 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.

KW - Chemical genomics

KW - Nucleolus

KW - Senescence

KW - Transcriptional damage response

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=84865303434&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865303434&partnerID=8YFLogxK

U2 - 10.1073/pnas.1206906109

DO - 10.1073/pnas.1206906109

M3 - Article

C2 - 22869755

AN - SCOPUS:84865303434

VL - 109

SP - 13799

EP - 13804

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 34

ER -