A Potential Role of Nuclear Matrix-associated Protein Kinase CK2 in Protection against Drug-induced Apoptosis in Cancer Cells

Abstract

Protein kinase CK2 (CK2) has long been implicated in the regulation of cell growth and proliferation. Its activity is generally elevated in rapidly proliferating tissues, and nuclear matrix (NM) is an important subnuclear locale of its functional signaling. In the prostate, nuclear CK2 is rapidly lost commensurate with induction of receptor-mediated apoptosis after growth stimulus withdrawal. By contrast, chemical-induced apoptosis in prostate cancer and other cells (by etoposide and diethylstilbestrol) evokes an enhancement in CK2 associated with the NM that appears to be because of translocation of CK2 from the cytoplasmic to the nuclear compartment. This shuttling of CK2 to the NM may reflect a protective response to chemical-mediated apoptosis. Supporting evidence for this was obtained by employing cells that were transiently transfected with various expression plasmids of CK2 (thereby expressing additional CK2) prior to treatment with etoposide or diethylstilbestrol. Cells transfected with the CK2␣ or CK2␣␤ showed significant resistance to chemical-mediated apoptosis commensurate with the corresponding elevation in CK2 in the NM. Transfection with CK2␤ did not demonstrate this effect. These results suggest, for the first time, that besides the commonly appreciated function of CK2 in cell growth, it may also have a role in protecting cells against apoptosis. Protein kinase CK2 (CK2)1 has been extensively studied in recent years for its potential role in multiple functional activities including the regulation of cell growth and proliferation. It is a ubiquitous protein Ser/Thr kinase, localized in the cell cytoplasm and nucleus, existing as a heterotetramer consisting of ␣, ␣Ј, and ␤ subunits (ϳ 42, 38, and 28 kDa, respectively) with the possible ␣ 2 ␤ 2 , ␣␣Ј␤ 2 , or ␣Ј␣Ј␤ 2 configuration. A number of putative substrates for CK2 have been identified in both the cytoplasm and the nucleus. Many of these are based on in vitro phosphorylation studies although a number of them have also been shown to be substrates for CK2 in vivo. Among the nuclear substrates are proteins involved in growth including RNA polymerases, topoisomerase II, protein B23, nucleolin, SV40 large T antigen, certain proto-oncogene products, and growth factors, as well as certain nonhistone proteins, which might include transcription factors, etc. (for examples see Refs. 1-10).In previous work, we have demonstrated that CK2 is dynamically regulated with respect to its nuclear localization, such that chromatin and NM appear to be its preferential sites of association within the nucleus. The association of CK2 in these compartments is profoundly responsive to the status of growth stimuli (1, 9, 11-13). To that end, we have employed androgen action in the prostate epithelial cells that is mediated via the androgen-receptor system as an experimental model. It is well known that withdrawal of androgenic growth signal via castration of adult rats induces rapid apoptosis in the epithelial cells of the gland and that this process is reversed on andro...

Protein kinase CK2 – A key suppressor of apoptosis

“…To provide a more direct confirmation of the role of CK2 as a suppressor of apoptosis we demonstrated that forced overexpression of CK2 prior to treatment of cells with etoposide or diethylstilbestrol strongly protected them against apoptosis (Guo et al, 2001). Analogous observations based on heat shock treatment of cells supported the role of CK2 in promoting cell survival Davis et al, 2002), and subsequent studies employing radiation or UV treatment of cells have made similar observations (Kato et al, 2003;Yamane and Kinsella, 2005).…”

Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts

“…CK2 is a ubiquitous and constitutively active serine/ threonine protein kinase that is implicated, among many other functions, in apoptosis, 22 cell survival 23 and cell transformation. 24 The antiapoptotic action of CK2 occurs through the phosphorylation of BID, a pro-apoptotic member of the BCL-2 family, which becomes resistant to caspase cleavage 25 and the phosphorylation of ARC (apoptotic repressor with caspase recruitment domain) that blocks the activity of caspase 8.…”

Protein kinase CK2 modulates apoptosis induced by resveratrol and epigallocatechin-3-gallate in prostate cancer cells

“…With respect to the proposed targeting of Akt by resveratrol and EGCG (1,3,41), it may be noted that a considerable amount of information on the regulation of PTEN by CK2 exists (42,43), and, indeed, it has been reported that CK2 can directly affect the phosphorylation of Akt (44). Overexpression of CK2 has been shown to block apoptosis mediated by DNAdamaging agents as well as via death receptors, whereas the reverse seems to be the case on down-regulation of CK2 by diverse means (8,14,15,45,46). Accordingly, our observations on the actions of resveratrol and EGCG on CK2 may have strong implications regarding their cell biological effects.…”