Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer

Abstract

Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4+ and CD8+ T cell percentages but increased CD4+CD25+ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4+ and CD8+ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8+ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8+ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros expression and function to maintain T cell homeostasis in murine PC.

Plant Flavone Apigenin: an Emerging Anticancer Agent

“…The decrease in Ikaros expression causes a reduction in the CD4+ and CD8+ T cell expression, and an increase in CD4+ CD25+ Tregs in tumor-bearing mice. In pancreatic cancer cells, CK2 regulates Ikaros expression, and apigenin has shown to stabilize Ikaros by downregulating CK2 to central T cell homeostasis [118]. …”

Casein kinase 2 inhibition impairs spontaneous and oxytocin‐induced contractions in late pregnant mouse uterus

“…In order to confirm that CK2 inhibition attenuates oxytocin‐induced contractions, we used another selective inhibitor of CK2, apigenin (Nelson et al., ). Apigenin at the same concentration (50 μ m ) inhibited the oxytocin response in the late pregnant uterine strips in a similar manner.…”

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

“…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). …”