It has been shown that the pro-inflammatory cytokine tumour necrosis factor-α (TNFα) induces rapid phosphorylation of IκBα and its ubiquitin-induced degradation. This event is necessary for NFκB/p65 to be released from the complex with IκBα and for its relocation to the nucleus where it exerts transactivation functions by binding co-activator proteins [reviewed in [39]]. As

incubation with PCP resulted in decreased phosphorylation of IKKβ-mediated phosphorylation of NFκB/p65 at the activating S536, we addressed the question whether PCP affected the TNFα-mediated translocation of NFκB/p65 into the nucleus. As shown in Fig. Epigenetics Compound Library high throughput 7, treatment of both cell lines with TNFα led to the accumulation of NFκB/p65 in the nucleus with respect to DMSO- and PCP-treated cells, respectively, where NFκB/p65 appeared

to localize in the cytoplasm. However, incubation of cells with PCP suppressed TNFα-induced migration of NFκB/p65 into the nucleus as indicated by the persistent signal in the cytoplasm. The study presented here, indicates that PCP is the active component of C11 exerting cytotoxic effects in human pancreatic cancer Selleckchem STA-9090 cell lines. Our previous studies showed that simultaneous silencing of the CK2 catalytic subunits by RNA interference enhances the sensitivity of these cell lines towards chemotherapeutic agents currently used in the clinics for the cure of advanced pancreatic cancer [[5], for a review see [40]]. We show here that PCP inhibits recombinant human CK2 in an ATP-competitive manner as well as the endogenously expressed enzyme as revealed by the decreased phosphorylation of the molecular chaperone Cdc37 at S13, a known cellular substrate target of CK2 [Fig. 6., [38]]. Evidence indicates that CK2 supports survival and confers resistance to chemotherapeutic treatment of cancer cells [reviewed in [2] and [6]]. Hence, PCP-mediated induction of cell death in human pancreatic cancer cells reported here, may be due, at least partially, to the inhibition of endogenous

CK2. However, as protein kinase CK2 expression levels have been shown to be elevated in cancer and highly proliferating cells, we cannot exclude that other types of cancer cells would respond to PCP treatment in a similar fashion. for The poor prognosis of pancreatic cancer is in part attributed to the presence of a subgroup of cancer stem cells which account for tumour recurrence due to their self-renewal, metastatic potential and resistance to cytotoxic drug treatment [19] and [20]. Interestingly, we show here that incubation of a sub-population of Panc-1 cells enriched in cancer stem cells with PCP induces a level of cytotoxicity comparable to the one observed in the cancer stem cells-depleted population suggesting that PCP treatment lowers the intrinsic resistance of cancer stem cells to cell death induction (Fig. 2).