Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin

Protein kinase CK2 is an antiapoptotic cancer-sustaining protein. Cur-cumin, reported previously as a CK2 inhibitor, is too bulky to be accom-modated in the CK2 active site and rapidly degrades in solution generatingvarious ATP-mimetic inhibitors; with a detailed comparative analysis, bymeans of both protein crystallography and enzymatic inhibition, ferulicacid was identified as the principal curcumin degradation product responsi-ble for CK2 inhibition. The other curcumin derivatives vanillin, feruloyl-methane and coniferyl aldehyde are weaker CK2 inhibitors. The highinstability of curcumin in standard buffered solutions flags this compound,which is included in many commercial libraries, as a possible source of mis-leading interpretations, as was the case for CK2. Ferulic acid does notshow any cytotoxicity and any inhibition of cellular CK2, due to its poorcellular permeability. However, curcumin acts as a prodrug in the cellularcontext, by generating its degradation products inside the treated cells, thusrescuing CK2 inhibition and consequently inducing cell death. Through theintracellular release of its degradation products, curcumin is expected toaffect various target families; here, we identify the first bromodomain ofBRD4 as a new target for those compounds.