Journal
CANCER LETTERS
Volume 384, Issue -, Pages 39-49Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.09.020
Keywords
ACC; AMPK; Cetuximab; EGFR; HIF-1; Warburg effect
Categories
Funding
- US National Institutes of Health [R01 CA179015, R21 DE021883]
- NATIONAL CANCER INSTITUTE [P30CA016672, R01CA179015] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [R21DE021883] Funding Source: NIH RePORTER
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Cetuximab inhibits HIF-1-regulated glycolysis in cancer cells, thereby reversing the Warburg effect and leading to inhibition of cancer cell metabolism. AMP-activated protein kinase (AMPK) is activated after cetuximab treatment, and a sustained AMPK activity is a mechanism contributing to cetuximab resistance. Here, we investigated how acetyl-CoA carboxylase (ACC), a downstream target of AMPK, rewires cancer metabolism in response to cetuximab treatment. We found that introduction of experimental ACC mutants lacking the AMPK phosphorylation sites (ACCl_S79A and ACC2_S212A) into head and neck squamous cell carcinoma (HNSCC) cells protected HNSCC cells from cetuximab-induced growth inhibition. HNSCC cells with acquired cetuximab resistance contained not only high levels of T172-phosphorylated AMPK and S79-phosphorylated ACC1 but also an increased level of total ACC. These findings were corroborated in tumor specimens of HNSCC patients treated with cetuximab. Cetuximab plus TOFA (an allosteric inhibitor of ACC) achieved remarkable growth inhibition of cetuximab-resistant HNSCC xenografts. Our data suggest a novel paradigm in which cetuximab-mediated activation of AMPK and subsequent phosphorylation and inhibition of ACC is followed by a compensatory increase in total ACC, which rewires cancer metabolism from glycolysis-dependent to lipogenesis-dependent. (C) 2016 Elsevier Ireland. Ltd. All rights reserved.
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