TY - JOUR
T1 - Inhibition of Cyclin-Dependent Kinase 8/Cyclin-Dependent Kinase 19 Suppresses Its Pro-Oncogenic Effects in Prostate Cancer
AU - Offermann, Anne
AU - Joerg, Vincent
AU - Becker, Finn
AU - Roesch, Marie C
AU - Kang, Duan
AU - Lemster, Anna-Lena
AU - Behrends, Jochen
AU - Merseburger, Axel S
AU - Culig, Zoran
AU - Sailer, Verena
AU - Brägelmann, Johannes
AU - Kirfel, Jutta
AU - Perner, Sven
N1 - Publisher Copyright:
© 2022 American Society for Investigative Pathology
Copyright © 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2022/5
Y1 - 2022/5
N2 - 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. Recently, we reported pro-oncogenic implications of the Mediator subunits cyclin-dependent kinase (CDK) 8 and 19 for the progression of PCa. In this study, the aim was to explore underlying molecular mechanisms and to test effects of novel CDK8/CDK19 inhibitors. PC3, DU145, LNCaP, and androgen-independent LNCaP Abl were used for in vitro experiments. Two inhibitors and CDK19 overexpression were used to modify CDK8/CDK19 activity. Thiazolyl blue tetrazolium bromide (MTT) assay, propidium iodide staining, wound healing assay, Boyden chambers, and adhesion assays in various experimental conditions 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 lead 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 pro-oncogenic effects, which is needed to develop CDK8/CDK19 as a therapeutic target in PCa.
AB - 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. Recently, we reported pro-oncogenic implications of the Mediator subunits cyclin-dependent kinase (CDK) 8 and 19 for the progression of PCa. In this study, the aim was to explore underlying molecular mechanisms and to test effects of novel CDK8/CDK19 inhibitors. PC3, DU145, LNCaP, and androgen-independent LNCaP Abl were used for in vitro experiments. Two inhibitors and CDK19 overexpression were used to modify CDK8/CDK19 activity. Thiazolyl blue tetrazolium bromide (MTT) assay, propidium iodide staining, wound healing assay, Boyden chambers, and adhesion assays in various experimental conditions 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 lead 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 pro-oncogenic effects, which is needed to develop CDK8/CDK19 as a therapeutic target in PCa.
UR - http://www.scopus.com/inward/record.url?scp=85128538492&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/1efe4149-6d87-352c-a5ff-f5c32042c86b/
U2 - 10.1016/j.ajpath.2022.01.010
DO - 10.1016/j.ajpath.2022.01.010
M3 - Journal articles
C2 - 35181333
SN - 0002-9440
VL - 192
SP - 813
EP - 823
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -