Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level

Abstract

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 b was equally expressed in the two cell variants, CK2a 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 CK2a 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.

Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

“…Some of these inhibitors such as 4,5,6,7-tetrabromobenzimidazole (TBI) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) inhibited the growth of malignant lymphoblastic leukemia cells with a better efficiency than Imatinib (17,18). Pharmacological downregulation of CK2 activity with specific inhibitors induced cell death in drug resistant R-CEM cells (19,20), human colon cancer cell lines and a breast cancer cell line (21). In the present study we demonstrate that TBI, DMAT and newly synthesized inhibitors MB01-3 and ZKK series have better efficacy towards malignant glioblastoma cells than the previously studied TBB.…”

“…Some of these inhibitors such as 4,5,6,7-tetrabromo-1H-benzimidazole (TBI) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) inhibited the growth of malignant lymphoblastic leukemia cells with a better efficiency than Imatinib, the well-known tyrosine kinase inhibitor (16)(17)(18). Downregulation of CK2 activity with specific inhibitors or silencing of CK2· expression induced cell death in drug-resistant R-CEM cells, overcoming the multidrug resistance phenotype (19,20). Inhibition of CK2 with 100 μM TBB or 20-40 μM DMAT significantly decreased viability and induced apoptosis of three human colon cancer and breast cancer cells in vitro (21).…”

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

“…This could rely on the observation that CK2 has been shown to increase the sensitivity of these tumor cells to chemotherapeutics. 47,59 Another scenario in which CK2 inhibition could be exploited is together with first and second generation BCR-ABL inhibitors, such as imatinib, dasatinib and nilotinib. Indeed, CK2 being an important target downstream of BCR-ABL, it likely contributes in sustaining the transformed phenotype promoted by this oncogenic fusion protein.…”

Reverse-phase protein microarrays (RPPA) as a diagnostic and therapeutic guide in multidrug resistant leukemia

“…Given these premises, we decided to perform a comparative analysis of the endogenous phosphorylome in two isogenic variants of human T lymphoblastoid CEM cell line, one sensitive to drug-induced apoptosis, while the other, referred to as MDR-CEM, derived from the parental one by selection with vinblastine treatment, and displaying a cross-resistance to many other chemotherapeutic drugs (26,27). In order to compare the phosphorylation profile of multiple proteins, we utilized the high throughput reversephase protein array technology (RPPA).…”