Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level.
Protein kinase CK2 is an ubiquitous and constitutively active kinase, which phosphorylates many cellular proteins and is implicated in the regulation of cell survival, proliferation and transformation. We investigated its possible involvement in the multidrug resistance phenotype (MDR) by analysing its level in two variants of CEM cells, namely S-CEM and R-CEM, normally sensitive or resistant to chemical apoptosis, respectively. We found that, while the CK2 regulatory subunit beta was equally expressed in the two cell variants, CK2alpha catalytic subunit was higher in R-CEM and this was accompanied by a higher phosphorylation of endogenous protein substrates. Pharmacological downregulation of CK2 activity by a panel of specific inhibitors, or knockdown of CK2alpha expression by RNA interference, were able to induce cell death in R-CEM. CK2 inhibitors could promote an increased uptake of chemotherapeutic drugs inside the cells and sensitize them to drug-induced apoptosis in a co-operative manner. CK2 blockade was also effective in inducing cell death of a different MDR line (U2OS). We therefore conclude that inhibition of CK2 can be considered as a promising tool to revert the MDR phenotype.
Di Maira
G
G
Department of Biological Chemistry and CNR Neuroscience Institute, University of Padova, Padova, Italy. maria.ruzzene@unipd.it
Brustolon
F
F
Bertacchini
J
J
Tosoni
K
K
Marmiroli
S
S
Pinna
L A
LA
Ruzzene
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D014162:Transfection; D014747:Vinblastine / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D034741:RNA, Small Interfering; D014747:Vinblastine; D004317:Doxorubicin; D047390:Casein Kinase II