Therapeutic CK2 inhibition attenuates diverse prosurvival signaling cascades and decreases cell viability in human breast cancer cells

Abstract

Breast cancer is the most common malignancy in women worldwide and remains a major cause of mortality, thus necessitating further therapeutic advancements. In breast cancer, numerous cell signaling pathways are aberrantly activated to produce the myriad phenotypes associated with malignancy; such pathways include the PI3K/Akt/mTOR, NF-κB and JAK/STAT cascades. These pathways are highly interconnected, but one prominent lateral enhancer of each is the remarkably promiscuous kinase CK2. CK2 expression has been shown to be elevated in cancer, thus implicating it in tumorigenesis through its effects on oncogenic signaling cascades. In this study, we identify aberrant expression of CK2 subunits in human breast samples from The Cancer Genome Atlas dataset. Additionally, two specific small molecule inhibitors of CK2, CX-4945 and TBB, were used to examine the role of CK2 in two human breast cancer cell lines, MDA-MB-231 and MCF-7 cells. We show that CK2 inhibition attenuates constitutive PI3K/Akt/mTOR, NF-κB and STAT3 activation and inducible NF-κB and JAK/STAT activation and downstream transcriptional activity. CX-4945 treatment caused a range of phenotypic changes in these cell lines, including decreased viability, cell cycle arrest, apoptosis and loss of migratory capacity. Overall, these results demonstrate the tremendous potential of CK2 as a clinical target in breast cancer.

Divergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity

“…Because CK2 readily phosphorylates recombinant HDAC3, we hypothesized that differential CK2 activity leads to the variation in HDAC3 phosphorylation. To test this hypothesis, we treated MDA-MB-231 cells with two structurally diverse kinase inhibitors that have been shown to potently inhibit CK2 activity (TBB, and LY294002) (Gray et al, 2014, Gharbi et al, 2007), followed by labeling with photomate. Neither of the compounds induced any change in HDAC3 engagement or phosphorylation state, despite significantly changing phosphorylation of CK2 substrates AKT or c-Jun (Figure S4b, Figure 6H, I).…”

Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia

“…Consistent with a role for CK2 in oncogenesis, increased levels of CK2 have been widely observed in various tumors, including lung, breast, prostate, head and neck, and colon cancers (Bliesath et al, 2012; Gray et al, 2014; Ruzzene et al, 2017; Wang et al, 2006; Yu et al, 2006; Zhang et al, 2009). …”

“…CK2 has been shown to control cell growth and proliferation by regulating cell cycle progression (Pinna and Meggio, 1997). CK2 also phosphorylates key proteins that possess anti-apoptotic functions, thus suppressing cellular apoptosis (Gray et al, 2014). The ability of CK2 to override cellular apoptotic signaling suggests a role in tumorigenesis and CK2 has been shown to aggressively increase tumor growth in most, if not all, cancer cells tested thus far (Guerra and Issinger, 1999; Meggio and Pinna, 2003; Nelson et al, 2017).…”

Genome Profiling for Aflatoxin B1 Resistance inSaccharomyces cerevisiaeReveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B1-associated DNA Damage

“…Mutations in PRKCSH and GANAB, human orthologs of GTB1 and ROT2, are linked to polycystic liver disease (Porath et al, 2016;Perugorria and Banales, 2017). The CKB2 ortholog, CSNK2B (Chua et al, 2017;Dotan et al, 2001;Zhang et al, 2015), is over-expressed in several liver cancers and therapeutics are currently in clinical trial (Gray et al, 2014, Li et al, 2017, Trembley et al, 2017. It is tempting to speculate that over-expression of CSNK2B also confers AFB 1 resistance.…”