Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer.
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.
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.
Nadine
N
Nelson
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.
Karoly
K
Szekeres
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.
Cristina
C
Iclozan
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.
Ivannie Ortiz
IO
Rivera
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.
Andrew
A
McGill
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.
Gbemisola
G
Johnson
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.
Onyekachi
O
Nwogu
Department of Molecular Medicine, University of South Florida, Tampa, Florida, United States of America.|Department of Immunology, Moffitt Cancer Center, Tampa, Florida, United States of America.
Tomar
http://orcid.org/0000-0003-0376-4586
T
Ghansah
D000818:Animals; D047310:Apigenin / Q000627:therapeutic use*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D007976:Leupeptins / Q000627:therapeutic use; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000627:therapeutic use; D054645:Protein Phosphatase 1 / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D007976:Leupeptins; D061988:Proteasome Inhibitors; D025521:Tumor Suppressor Proteins; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D047310:Apigenin; D047390:Casein Kinase II; D054645:Protein Phosphatase 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde