Mounting evidence suggests that there may be multiple nuclear and cytoplasmic targets that impact on the apoptotic machinery in response to modulations in CK2. For example, caspases 2, 3, 8, and 9 respond to alteration in the CK2 signal in diverse manners (Shin et al., 2005
; Wang et al., 2006a
). Procaspase-2 was shown to be a target of CK2 such that its dephosphorylation results in its dimerization and activation (Shin et al., 2005
). ARC, a protein that inhibits caspase-8 activity when phosphorylated, has also been identified as a CK2 target (Li et al., 2002
). The hallmark of nuclear apoptotic activity indicated by lamin A cleavage is strongly elicited by downregulation of CK2 and prevented by its forced overexpression (Ahmad et al., 2006
; Wang et al., 2006a
). Among the Bcl-2 family, Bid has been shown to be phosphorylated by CK2 (and also CK1) at serine residues in the vicinity of caspase-8 recognition site thereby preventing its cleavage by activated caspase-8 (Desagher et al., 2001
). In a preliminary observation, we noted that forced overexpression of CK2 in ALVA-41 prostate cancer cells caused an upregulation of Bid (Ahmed, et al.
, unpublished results). Subsequent studies have shown Bid to be an interaction partner of the catalytic subunit CK2α (Olsen et al., 2006
). In our studies employing TRAIL as inducer of apoptosis in prostate cancer cells, we have found Bcl-xL and Bcl-2 proteins to be sensitive to CK2 status altered by treating cells with chemical inhibitors of CK2 (Wang et al., 2006a
). Inhibition or downregulation of CK2 results in loss of Bcl-xL and Bcl-2 proteins with Bax being upregulated, whereas overexpression of CK2 results in prevention of such changes in these proteins (Wang et al., 2006a
). The engagement of the mitochondrial pathway is clearly indicated by the alterations in cytochrome c
release upon downregulation of CK2 while it is blocked by overexpression of CK2 (Wang et al., 2006a
). These various studies suggest that mitochondrial pathway plays a role in CK2 regulation of apoptotic activity and that certain of the Bcl-2 family of proteins in the apoptotic machinery are among the targets of CK2.
Attempts to identify proximal effectors of CK2 mediated modulation of apoptosis have revealed that intracellular H2
production upon downregulation of CK2 in prostate cancer cells may be an important signal for induction of apoptosis under these conditions (Ahmad et al., 2006
). These studies have shown that downregulation of CK2 by employing chemical inhibitors of CK2 or antisense CK2α or siRNA for CK2α to achieve downregulation of CK2 in prostate cancer cells (both androgen-sensitive ALVA-41 and –insensitive PC-3 cells) results in rapid increase in intracellular H2
which may be responsible for triggering the downstream pathways resulting in release of cytochrome c
, activation of caspase-3, downregulation of IκB, translocation of NF-κB p65, and subsequent DNA fragmentation. These novel observations implicate a relationship between reactive oxygen species and CK2 such that inhibition of CK2 may result in elevation of intracellular H2
leading to activation of its downstream targets in the apoptotic machinery (Ahmad et al., 2006
). In this context, it is of interest to note that SAG (sensitive to apoptosis gene) protein which is upregulated on hypoxia induction undergoes degradation on phosphorylation by CK2 at Thr-10 (He et al., 2007
Another locus of CK2 mediated modulation of apoptotic activity appears to be the inhibitor of apoptosis proteins (IAPs). Among these, survivin has been shown to be influenced by the CK2 status in cells (Tapia et al., 2006
). In accord with these observations, ongoing work in our laboratory has also shown that survivin expression cIAPs expression is reduced in prostate cancer cells upon downregulation of CK2; further, we have observed that cIAP1, cIAP2, and xIAP are also engaged downstream of the CK2 signal (Ahmed et al.
, unpublished data).
Certain other genes that play a role in apoptosis are also affected by CK2. For example, in studies on TRAIL mediated induction of apoptosis, we observed downregulation of cFLIPL
which was prevented by overexpression of CK2 in PC-3 prostate cancer cells (Wang et al., 2006a
); the significance of this observation may relate to the recent documentation that cFLIPL
expression is necessary and sufficient to maintain resistance to TRAIL-induced apoptosis in prostate cancer cells (Zhang et al., 2004
). Upon phosphorylation by CK2, Max is rendered insensitive to cleavage by caspases (Krippner-Heidenreich et al., 2001
) while Myc is stabilized by CK2 mediated phosphorylation (Channavajhala and Seldin, 2002
). In the NF-κB pathway, downregulation of CK2 by employing antisense CK2α resulted in nuclear translocation of NF-κB p65 (Ahmad et al., 2006
). Promotion of aberrant activation of nuclear factor-κB by CK2 in transformed phenotype of breast cancer cells has been documented (Romieu-Mourez et al., 2002
; Eddy et al., 2005
). Aberrant NF-κB activation by serum factors involving CK2 mediated activation of IKK2 has been reported in head and neck squamous carcinoma cells (Yu et al., 2006
). Likewise, CK2 has been found to phosphorylate the Fas-associated factor FAF1 in vivo and influence its translocation to the nucleus (Olsen et al., 2003
). A recent study has demonstrated that IGFBP-3 which is known to promote apoptosis in cancer cells is a substrate for CK2 mediated phosphorylation at ser-167, and that phosphorylation of this site by CK2 limits the ability of IGFBP-3 to induce apoptosis in prostate cancer cells (Cobb et al., 2007
). Analogous to these studies is the recent documentation that PML tumor suppressor which controls key pathways of growth suppression, induction of apoptosis and cellular senescence loses can undergo phosphorylation by CK2 at ser-517 which results in its ubiquitin-mediated degradation. These authors also found an inverse relation between CK2 and PML protein level in human lung cancer (Scaglioni et al., 2006
). PTEN, another important signal related to cell death and survival, appears to be stabilized on phosphorylation by CK2 (Vazquez et al., 2001
). In this context, it is interesting to note that AKT (a protein kinase with a role in cell survival) which requires phosphorylation at Ser-473 and Thr-308 by cognate kinases for its activation also has been found to harbor a CK2-specific phosphorylation site at Ser-129 that appears to contribute to its hyperactivation (Di Maira et al., 2005
). In a preliminary study, we also noted that forced overexpression of CK2 influenced AKT activation in ALVA-41 prostate cancer cells (Ahmed et al.
, unpublished data). Further support for the interaction of CK2 and AKT has been provided in a recent report (Guerra, 2006