Comparative analysis of CK2 expression and function in tumor cell lines displaying sensitivity vs. resistance to
Giovanni Di Maira1, Francesca Brustolon, Kendra Tosoni
1Department of Biological Chemistry and CNR Neuroscience Institute, University of Padova, Viale G. Colombo, 3, 35121, Padova, Italy.
Abstract:
CK2 is a pleiotropic protein kinase, which phosphorylates many substrates and has a global role in promoting cell survival and preventing apoptosis. In this study, we investigated its involvement in the phenomenon of the drug resistance, by which tumor cells frequently become unresponsive to chemical apoptosis. By comparing the expression of CK2 subunits in four different pairs of sensitive (S) and resistant (R) cancer cell lines, we found that in three cases the resistant phenotype is accompanied by the overexpression of the CK2 catalytic alpha subunit, either alone or in combination with the regulatory beta subunit. The degree of CK2 expression correlates with the CK2 catalytic activity, when measured toward endogenous protein substrates. All the tested R cell lines, including the one with no CK2 overexpression, can be induced to undergo death by treatment with CK2 inhibitors. We therefore conclude that, although CK2 overexpression is not an absolute requirement for the resistant phenotype, its activity is essential for cell survival and contributes to a high degree of resistance. We also found that CK2 inhibition increases the accumulation of cytotoxic drugs inside the R cells, presumably by impairing the functionality of the extrusion pump P-gp. We therefore propose that CK2 should be considered a target to counteract the pharmaco-resistant phenotype.
Insights
Protein kinase CK2 (Casein kinase 2) activity is essential for cancer cell survival and drug resistance. Inhibiting CK2 can re-sensitize resistant tumors to chemotherapy and reduce drug efflux.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Protein kinase CK2 (CK2) is crucial for cell survival and inhibits apoptosis.
- Cancer cells frequently develop drug resistance, becoming unresponsive to chemotherapy.
- The role of CK2 in mediating tumor drug resistance requires further investigation.
Purpose of the Study:
- To investigate the involvement of CK2 in acquired drug resistance in cancer.
- To determine if CK2 overexpression or activity correlates with the resistant phenotype.
- To evaluate the therapeutic potential of CK2 inhibitors in overcoming drug resistance.
Main Methods:
- Comparative analysis of CK2 subunit expression in sensitive and resistant cancer cell lines.
- Measurement of CK2 catalytic activity using endogenous substrates.
- Treatment of resistant cell lines with CK2 inhibitors and assessment of cell death.
- Evaluation of drug accumulation in resistant cells following CK2 inhibition.
Main Results:
- Resistant cancer cell lines often overexpress CK2 alpha and/or beta subunits.
- CK2 expression levels correlate with its catalytic activity.
- CK2 inhibition induces apoptosis in all tested resistant cell lines, irrespective of CK2 overexpression.
- CK2 inhibition enhances intracellular accumulation of cytotoxic drugs by potentially inhibiting P-glycoprotein (P-gp).
Conclusions:
- CK2 activity is essential for cancer cell survival and contributes significantly to drug resistance.
- While not always overexpressed, CK2's enzymatic function is critical for the resistant phenotype.
- Targeting CK2 with inhibitors presents a promising strategy to overcome drug resistance and improve chemotherapy efficacy.
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