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Targeting CK2 by small molecule inhibitor DMAT modulates NF-kappa B and TP53 signaling, survival and migration in head and neck cancer

Matthew Brown, Reza Ehsanian, Pattatrheyil Arun, Zhong Chen, Carter Van Waes
University Hospitals
2010-03-29

Presenter: Matthew Brown

Affidavit:

Director Name:

Author Category: Resident/Fellow
Presentation Category: Basic Science Research
Abstract Category: Craniomaxillofacial

Objective: Upregulated CK2 activity is implicated in promoting the malignant phenotype and progression of head and neck squamous cell carcinoma (HNSCC). We previously identified CK2 as an upstream kinase activating NF-kappaB prosurvival and repressing TP53/TAp63 tumor suppressor transcription factors. Here, we investigate the molecular and anti-tumor effects of targeting CK2 with a small molecule inhibitor, DMAT (2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole).

Design: Cell lines used were from a panel of 9 University of Michigan squamous cell carcinoma (UMSCC) cell lines. Cell proliferation was measured by MTT assay. Cell cycle and induction of cell death were measured by DNA flow cytometry. The activity of NF-kappaB, IL-8 and BCL-XL promoters were tested by the chemiluminescent reporter gene assay, and gene expression was examined by QRT-PCR. Cell migration was measured by a wound healing assay.

Results: Concentrations as low as 10uM DMAT significantly inhibited proliferation, modulated cell cycle, and induced cell death in a dose dependent manner. 20uM DMAT inhibited cell migration at the early time point, and 40uM exhibited complete inhibition. CK2 inhibition with DMAT downregulated genes promoting survival, inflammation, angiogenesis, and adhesion, such as BCL-XL, IL-8, VEGF and ITGB4. DMAT upregulated two genes promoting apoptosis, TP53 and TAp63, and two E-cadherins which suppress invasion and metastasis.

Conclusions: Our study reveals the novel effects of small molecule DMAT targeting CK2 in co-regulating NF-kappaB, TP53 and other signaling pathways, as w

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