Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab

Autor: Xudong Wang, Zhen Fan, Yun Hong, Songbo Qiu, Qiang Li, Yang Lu, Lun Zhang, Bharat Kumar Reddy Chaganty, Jingtao Luo
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Cancer Research
Time Factors
Cetuximab
AMP-Activated Protein Kinases
chemistry.chemical_compound
0302 clinical medicine
AMP-activated protein kinase
Antineoplastic Combined Chemotherapy Protocols
Enzyme Inhibitors
Phosphorylation
Aged
80 and over
biology
Middle Aged
Warburg effect
Oncology
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Carcinoma
Squamous Cell
Female
RNA Interference
Growth inhibition
Glycolysis
Signal Transduction
medicine.drug
Adult
medicine.medical_specialty
Cell Survival
Lipolysis
Mice
Nude
Antineoplastic Agents
Transfection
Article
03 medical and health sciences
Cell Line
Tumor
Internal medicine
medicine
Animals
Humans
neoplasms
Aged
Cell Proliferation
Squamous Cell Carcinoma of Head and Neck
Acetyl-CoA carboxylase
AMPK
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
Xenograft Model Antitumor Assays
Head and neck squamous-cell carcinoma
digestive system diseases
stomatognathic diseases
030104 developmental biology
Endocrinology
chemistry
Drug Resistance
Neoplasm
Mutation
Cancer cell
biology.protein
Cancer research
Acetyl-CoA Carboxylase
Zdroj: Cancer Letters. 384:39-49
ISSN: 0304-3835
DOI: 10.1016/j.canlet.2016.09.020
Popis: 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 (ACC1_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.
Databáze: OpenAIRE
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