CK2 modulation of NF-kappaB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules.
OBJECTIVE
The aim of this study is to investigate the expression of CK2 subunits and CK2 effects on NF-kappaB-mediated and TP53-mediated signal activation and gene expression, the malignant phenotype, and chemosensitivity in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo.


METHODS
Protein expression of CK2 subunits was investigated by Western blot and immunohistochemistry. CK2 subunits were knocked down by small interfering RNA, and NF-kappaB activation was examined using DNA binding, Western blot, and luciferase reporter assays. Gene expression was measured by quantitative reverse transcription-PCR. Cell growth, survival, motility, and sensitivity to cisplatin were measured by MTT, flow cytometry, and migration assays. In vivo targeting of CK2alpha/alpha' in HNSCC xenograft models was achieved using anti-CK2alpha/alpha' oligodeoxynucleotide encapsulated in sub-50-nm tenfibgen nanocapsules.


RESULTS
CK2 subunit proteins were overexpressed in HNSCC lines and tissues. Knockdown of CK2 subunits differentially inhibited IkappaBalpha degradation, NF-kappaB nuclear localization, phosphorylation, DNA binding, and reporter activity. CK2 subunits modulated gene expression and the malignant phenotype involved in cell cycle and migration, whereas CK2alpha is critical to promote proliferation, antiapoptosis, and cisplatin resistance in vitro. Furthermore, in vivo delivery of anti-CK2alpha/alpha' oligodeoxynucleotide nanocapsules significantly suppressed tumor growth in HNSCC xenograft models, in association with modulation of CK2 and NF-kappaB regulated molecules, TP53 family proteins, and induction of apoptosis.


CONCLUSIONS
Our study reveals a novel role of CK2 in coregulating NF-kappaB activation, TP53/p63 expression, and downstream gene expression. Downregulation of CK2 in HNSCC models in vitro and in vivo shows antitumor effects as well as sensitization to cisplatin.
Brown
Matthew S
MS
Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892-1419, USA.
Diallo
Oumou T
OT
Hu
Michael
M
Ehsanian
Reza
R
Yang
Xinping
X
Arun
Pattatheyil
P
Lu
Hai
H
Korman
Vicci
V
Unger
Gretchen
G
Ahmed
Khalil
K
Van Waes
Carter
C
Chen
Zhong
Z
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053769:Nanocapsules; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
D016328:NF-kappa B; D053769:Nanocapsules; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D047390:Casein Kinase II