Involvement of reactive oxygen species in apoptosis induced by pharmacological inhibition of protein kinase CK2.
It has been reported that inhibition of protein kinase CK2 (CK2) with antisense oligodeoxynucleotides (ODN) is a potent inducer of apoptosis in cancer cells but not in normal cells. In this regard, the apoptotic-inducing effect is attributed to the catalytic activity of the enzyme, which phosphorylates proapoptotic proteins to inhibit their functions. In this study we investigate the role of intracellular redox status in the proapoptotic activity of CK2 inhibition in human leukemia Cem cells. We provide evidence that inhibition of CK2 activity induces apoptotic cell death as evident by activation of caspase 3, DNA fragmentation, and phosphatidylserine externalization. Inhibition of CK2 resulted in a significant increase in intracellular hydrogen peroxide production, which we show as a critical mediator of apoptosis. To that end, apoptotic hallmarks, like DNA fragmentation and phosphatidylserine externalization, were blocked with the specific hydrogen peroxide scavenger catalase. We also show that inhibition of CK2 reduces cytosolic intracellular superoxide, a precursor of hydrogen peroxide. In summary, decreasing CK2 activity increases intracellular hydrogen peroxide, creating an intracellular environment conducive for death execution. Taken together, these data provide information on novel pathways involved in CK2 biology with implications for effective tools against drug-resistant tumors.
Hanif
Ismail M
IM
National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore.
Ahmad
Kashif A
KA
Ahmed
Khalil
K
Pervaiz
Shazib
S
D017209:Apoptosis / Q000187:drug effects*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
C405354:4,5,6,7-tetrabromobenzotriazole; D017382:Reactive Oxygen Species; D014230:Triazoles; D013481:Superoxides; D006861:Hydrogen Peroxide; D047390:Casein Kinase II