Critical Role of Intracellular Redox Status in Apoptosis Mediated By Inhibition of Protein Kinase CK2 in Cancer Cells

Abstract

<P>IN THIS THESIS, WE PROVIDE EVIDENCE THAT INHIBITION OF CK2 ACTIVITY INDUCES APOPTOTIC CELL DEATH IN HUMAN LEUKEMIA CELLS AS EVIDENT BY CASPASES ACTIVATION, PS EXTERNALIZATION AND DNA FRAGMENTATION. INHIBITION OF CK2 RESULTS IN A SIGNIFICANT DECREASE IN CYTOSOLIC SUPEROXIDE WITH THE CONCOMITANT INCREASE IN INTRACELLULAR HYDROGEN PEROXIDE, WHICH IS CRITICAL FOR APOPTOSIS. WE ALSO SHOW THAT OVEREXPRESSION OF CK2 CONFERS CHEMOTHERAPEUTIC RESISTANCE TO THE CELLS BY INDUCING AN INTRACELLULAR PRO-OXIDANT STATE. WE FURTHER ILLUSTRATE THAT INHIBITION OF CK2 MANIPULATES THE CELLULAR REDOX STATUS INDEPENDENT OF THE MITOCHONDRIA BUT RE-ACTIVATES CU/ZN SOD BY DISSOCIATING ITS INTERACTION WITH CK2 WHICH INHIBITS THE DISMUTATION ACTIVITY OF THE FORMER. WE ALSO SHOW THAT CK2 INHIBITORS DEMONSTRATE TUMOR SELECTIVE ACTIVITY BY INDUCING ROS PRODUCTION AND APOPTOSIS IN MALIGNANT TUMORS. FINALLY, WE ALSO SHOW THAT TBB SYNERGIZE THE APOPTOTIC EFFECT OF CHEMOTHERAPEUTIC AGENT THROUGH ROS BURST IN A COMBIN