CK2 inhibition induces apoptosis via the ER stress response.
Protein kinase CK2 is a ubiquitously expressed serine/threonine kinase consisting of two catalytic α/α' and two regulatory β subunits. Expression of CK2 is highly elevated in tumor cells where it protects cells from apoptosis. Accordingly inhibition of CK2 is known to induce programmed cell death, making it a promising target for cancer therapy. In the present study we investigated apoptosis induction by the CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) in prostate tumor cells. In contrast to PC-3 cells LNCaP cells respond to CK2 inhibition with apoptosis. Most interestingly we found the mitochondrial pathway induced in LNCaP as well as in PC-3 cells as monitored by down-regulation of bcl-2 and subsequent cytochrome c release. In both cell lines activation of caspase 9 was not detected. Instead, an activation of the endoplasmic reticulum (ER) stress response in LNCaP cells after treatment with the CK2 inhibitor TBB was found. We show that this ER stress response led to an up-regulation of the death receptor DR5 and subsequent apoptosis in LNCaP cells.
Hessenauer
Andrea
A
Allgemeine Zoologie und Endokrinologie, Universität Ulm, Ulm, Germany. andrea.hessenauer@uni-ulm.de
Schneider
Carolin C
CC
Götz
Claudia
C
Montenarh
Mathias
M
D017209:Apoptosis; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D056811:Unfolded Protein Response
C405354:4,5,6,7-tetrabromobenzotriazole; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014230:Triazoles; D051742:Transcription Factor CHOP; D045304:Cytochromes c; D047390:Casein Kinase II; D053453:Caspase 9