Universität zu Köln

Offermann, Anne, Joerg, Vincent, Becker, Finn, Roesch, Marie C., Kang, Duan, Lemster, Anna-Lena, Tharun, Lars, Behrends, Jochen ORCID: 0000-0002-0648-8911, Merseburger, Axel S., Culig, Zoran, Sailer, Verena, Braegelmann, Johannes, Kirfel, Jutta and Perner, Sven (2022). Inhibition of Cyclin-Dependent Kinase 8/Cyclin-Dependent Kinase 19 Suppresses Its Pro-Oncogenic Effects in Prostate Cancer. Am. J. Pathol., 192 (5). S. 813 - 824. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1525-2191

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Abstract

Progression of prostate cancer (PCa) is characterized by metastasis and castration resistance after response to androgen deprivation. Therapeutic options are limited, causing high morbidity and lethality. Recent work reported pro-oncogenic implications of the Mediator subunits cyclin-dependent kinase (CDK) 8 and 19 for the progression of PCa. The current study explored the underlying molecular mechanisms of CDK8/CDK19 and tested effects of novel CDK8/CDK19 inhibitors. PC3, DU145, LNCaP, and androgen-independent LNCaP Abl were used for in vitro experiments. Two inhibitors and CDK19 over expression were used to modify CDK8/CDK19 activity. MTT assay, propidium iodide staining, wound healing assay, Boyden chamber assay, and adhesion assay were used to investigate cell viability, cell cycle, migration, and adhesion, respectively. Peptide-kinase screen using the PamGene platform was conducted to identify phosphorylated targets. Combining CDK8/CDK19 inhibitors with anti-androgens led to synergistic antiproliferative effects and sensitized androgen-independent cells to bicalutamide. CDK8/CDK19 inhibition resulted in reduced migration and increased collagen I-dependent adhesion. Phosphorylation of multiple peptides linked to cancer progression was identified to be dependent on CDK8/CDK19. In summary, this study substantially supports recent findings on CDK8/ CDK19 in PCa progression. These findings contribute to a better understanding of underlying prooncogenic effects, which is needed to develop CDK8/CDK19 as a therapeutic target in PCa.& nbsp;

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Offermann, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Joerg, Vincent UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Finn UNSPECIFIED UNSPECIFIED UNSPECIFIED Roesch, Marie C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kang, Duan UNSPECIFIED UNSPECIFIED UNSPECIFIED Lemster, Anna-Lena UNSPECIFIED UNSPECIFIED UNSPECIFIED Tharun, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Behrends, Jochen UNSPECIFIED orcid.org/0000-0002-0648-8911 UNSPECIFIED Merseburger, Axel S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Culig, Zoran UNSPECIFIED UNSPECIFIED UNSPECIFIED Sailer, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Braegelmann, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirfel, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Perner, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-685381
DOI:	10.1016/j.ajpath.2022.01.010
Journal or Publication Title:	Am. J. Pathol.
Volume:	192
Number:	5
Page Range:	S. 813 - 824
Date:	2022
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1525-2191
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ANDROGEN RECEPTOR; MEDIATOR COMPLEX; CDK8; PHOSPHORYLATION; BICALUTAMIDE; POTENT; CELLS; PROGRESSION; ANTAGONIST; STAT1 Multiple languages Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68538