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

Abstract

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.

AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis

“…Western blot analysis was performed using the enhanced chemiluminescence detection kit (Amersham Biosciences) after incubation of the nitrocellulose membrane with various primary antibodies and horseradish peroxidase-labeled secondary antibodies [39–41]. Immunoprecipitation was performed by subjecting cell lysates to reaction with respective primary antibodies and protein A sepharose beads (Amersham Biosciences) at 4°C overnight.…”

“…Hematoxylin was used for cell nuclear counterstaining. ImageJ image processing tool was used to quantify relative ASCT2 expression in cells after various treatments [41–46]. …”

Identification of Cancer–associated metabolic vulnerabilities by modeling multi-objective optimality in metabolism

“…The finding about the contradictory roles of the ambiguous enzymes in promoting cell proliferation and suppressing the Warburg effect was also supported by several lines of literature-based evidence. For instance, the model-predicted ambiguous enzyme, acetyl-CoA carboxylase (ACC), was shown to shift cancer metabolism from glycolysis-dependent to lipogenesis-dependent in human head and neck squamous cell carcinoma (HNSCC) cells [47] and suppress whole-body glycolysis in high-fat-fed mice [48], while its inhibition impaired proliferation of human prostate cancer cells [49]. Another model-predicted ambiguous enzyme, proline dehydrogenase (PRODH/POX), was shown to suppress lactate production in human colon cancer cells [50], while its inhibition impaired proliferation of human lung cancer cells [51] and breast cancer cells [52].…”

Lipid Synthesis Is a Metabolic Liability of Non–Small Cell Lung Cancer

“…Short interfering RNA (siRNA) knockdown of ACC1 expression induced apo- ptosis in prostate (Brusselmans et al 2005) and breast (Chajes et al 2006) cancer cells and in cisplatin-resistant lung cancer cell lines (Wangpaichitr et al 2012), and chemical inhibition of ACC1 and ACC2 by the macrocyclic myxobacterial natural product Soraphen A led to growth arrest in breast cancer cells (Beckers et al 2007) and induction of apoptosis in prostate cancer cells (Corominas-Faja et al 2014). Constitutively active ACC mutants also protected head and neck squamous cancer cells from cetuximab-induced growth inhibition (Luo et al 2016). However, although these observations provide compelling data that ACC mediates cellular proliferation, these studies were exclusively in vitro and did not address whether ACC activation was required for tumor growth in vivo, as the genetic role of ACC in tumor growth had not been investigated.…”