Protein kinase CK2 inhibition induces cell death via early impact on mitochondrial function

Protein kinase CK2 is a highly conserved and ubiquitous protein Ser/Thr kinase consisting of two catalytic subunits α and α′ and two regulatory β subunits with the catalytic subunits linked through the β subunits. CK2 has been found to play a role in a vast number of normal and abnormal cell functions and has emerged as a key cellular regulator with a large number of substrates [Ahmed, 1999; Guerra and Issinger, 1999; Meggio and Pinna, 2003; Pinna, 2002; St-Denis and Litchfield, 2009; Tawfic et al., 2001]. In particular, much work has been undertaken regarding its function in cancer pathobiology and it is remarkable that CK2 has been found to be uniformly dysregulated in all cancers examined [Ahmed et al., 2000; Guerra and Issinger, 2008; Tawfic et al., 2001; Trembley et al., 2009]. While it was known for a long time that CK2 was elevated in rapidly growing normal and cancer cells, its role in cancer cells was unclear. We demonstrated that CK2, in addition to its role in cell growth and proliferation, is also a potent suppressor of apoptosis; further, the CK2α catalytic subunit is responsible for the majority of the apoptosis suppression [Ahmad et al., 2008; Ahmed et al., 2002; Guo et al., 2001; Tawfic et al., 2001]. Thus, the latter characteristic of CK2 provided an important link of this kinase to the cancer cell phenotype as continued cell proliferation and resistance to cell death are two consistent features of cancer cell biology [Hanahan and Weinberg, 2011]. Much evidence has suggested that elevated CK2 levels have a broad role in cell death suppression mediated through diverse signals [Ahmad et al., 2008]. In this context, we demonstrated that one mode of CK2 mediated suppression of apoptosis involves the mitochondrial apoptotic circuitry. In these studies, we observed that downregulation of CK2 resulted in upregulation of Bax and downregulation of Bcl-2 and Bcl-xL accompanied with release of cytochrome c. These events were completely blocked when forced overexpression of CK2α was instituted [Wang et al., 2005a; Wang et al., 2006]. In subsequent studies it was observed that downregulation of CK2 activity or expression in prostate cancer cells for 6–24 h either by chemical inhibition or use of antisense to CK2α resulted in production of H2O2 hinting that this may initiate apoptotic signaling under these conditions [Ahmad et al., 2006]. However, the mechanism underlying the induction of apoptosis following downregulation of CK2 is not fully understood, especially with respect to the earliest events that occur upon inhibition of CK2. Here we have examined the effect of CK2 inhibition on mitochondrial function and observed that, following the treatment of cells with a chemical inhibitor of CK2, a change in the mitochondrial membrane potential (Δψm) is detected as early as 2 h, thus occurring significantly prior to activation of other apoptotic signals. While CK2 is known to be localized in the nuclear and cytoplasmic fractions, we have also identified its presence in prostate cell mitochondria. Further, our results provide evidence for the first time suggesting that inhibition of mitochondrial CK2 may be involved in causing rapid loss of Δψm as a primary event that triggers the mitochondrial apoptotic circuitry under these conditions.