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Background: Accumulating evidence shows that high expression of casein kinase 2 (CK2) and phosphorylated acetyl CoA carboxylase (pACC) in patients with squamous cell carcinoma of the head and neck (SCCHN) correlates with decreased survival rates. Computational analysis has shown that ACC is a potential substrate for CK2, and its inhibition can suppress ACC phosphorylation in vitro. CX-4945, also known as silmitasertib, is an orally administered, highly specific, ATP-competitive inhibitor of CK2 and is under clinical investigation as a treatment for malignancies. We hypothesize that inhibition of CK2 by CX-4945 can reduce CK2-downstream phosphorylation of ACC as a therapeutic strategy against SCCHN.Methods: Three aggressive SCCHN cell lines (OSC-19, FaDu and HN31) were cultured to investigate the anticancer mechanism of the CK2 inhibitor, CX-4945. Cell cycle analysis, Annexin V/PI staining, and cleavage of PARP were performed to detect apoptosis. Western blot, electron microscopy and analysis of acidic vesicular organelle development were used to detect autophagy. Interference with cellular metabolism by CX-4945 treatment was determined by Seahorse XF24 Extracellular Flux Analyzer and mass spectrometry.Results: Cellular metabolism was impeded by CX-4945 in aggressive SCCHN cells by Seahorse XF24 Extracellular Flux Analyzer and mass spectrometry, and consequently time- and dose-dependent lipid droplet accumulation and non-apoptotic cell death were observed. The lipogenic enzyme ACC was demonstrated to be associated with CK2, and its repressive phosphorylation could be removed by the CK2 inhibitor CX-4945. Overexpression of ACC resulted in impaired cell survival following transient transfection.Conclusion: The findings demonstrate that CK2 inhibition impairs normal cellular energy metabolism and may be an attractive therapy for treating aggressive SCCHN. [ABSTRACT FROM AUTHOR]