Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab.
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.
Department of Head and Neck Surgical Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jingtao
J
Luo
Department of Oral Medicine, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong 510055, China; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yun
Y
Hong
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yang
Y
Lu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Songbo
S
Qiu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bharat K R
BK
Chaganty
Department of Head and Neck Surgical Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China.
Lun
L
Zhang
Department of Head and Neck Surgical Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China.
Xudong
X
Wang
Department of Head and Neck Surgical Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China.
Qiang
Q
Li
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: zfan@mdanderson.org.
Zhen
Z
Fan
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006019:Glycolysis / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D055372:AMP-Activated Protein Kinases; C000588423:ACACA protein, human; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase; D000068818:Cetuximab
ACC; AMPK; Cetuximab; EGFR; HIF-1; Warburg effect
Ann Oncol. 2012 Sep;23 Suppl 10:x178-85
22987958
Science. 1956 Feb 24;123(3191):309-14
13298683
PLoS One. 2010 Dec 29;5(12):e15823
21209911
J Cell Mol Med. 2009 Sep;13(9A):2780-6
19674190
Biotechniques. 2013 Jul;55(1):28-33
23834382
Cancer Lett. 2012 Sep 1;322(1):78-85
22348829
Cell Cycle. 2014;13(9):1400-12
24626186
Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
22436748
Oncotarget. 2016 Oct 4;7(40):64766-64777
27074568
Dev Cell. 2010 Apr 20;18(4):533-43
20412769
J Appl Physiol (1985). 1997 Jan;82(1):219-25
9029219
Cell. 2011 Mar 4;144(5):646-74
21376230
Nat Rev Drug Discov. 2011 Aug 31;10(9):671-84
21878982
Oncogene. 2005 Jun 23;24(27):4433-41
15806152
Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12564-9
20538976
Oncogene. 2010 Feb 4;29(5):625-34
19946328
Cancer Res. 2010 Jul 15;70(14 ):5942-52
20634405
Cancer Cell. 2010 Nov 16;18(5):423-35
21075308
Nature. 2012 May 09;485(7400):661-5
22660331
Cancer Biol Ther. 2014 Jan;15(1):89-98
24100272
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Oncotarget. 2015 May 10;6(13):11507-18
25871473
J Clin Invest. 2002 Dec;110(11):1687-93
12464674
J Lipid Res. 2009 Apr;50 Suppl:S138-43
19047759
FASEB J. 2004 Jun;18(9):1028-30
15084514
Anat Rec (Hoboken). 2013 Mar;296(3):378-81
23382140
Cell Metab. 2013 Aug 6;18(2):153-61
23791484
Mol Cancer Ther. 2008 May;7(5):1207-17
18483308
Lipids. 1984 Nov;19(11):851-6
6549204
J Biol Chem. 1979 Oct 25;254(20):10095-101
39932
J Biol Chem. 1994 Sep 2;269(35):22162-8
7915280
EMBO J. 2004 May 5;23 (9):1949-56
15071503
J Cell Sci. 2004 Nov 1;117(Pt 23):5479-87
15509864
Science. 2009 May 22;324(5930):1029-33
19460998
Curr Opin Genet Dev. 2010 Feb;20(1):51-6
19942427
Clin Cancer Res. 2011 Dec 1;17(23):7248-64
21868764
Biochem Biophys Res Commun. 2009 Jul 31;385(3):302-6
19450551
Mol Cancer Ther. 2013 Oct;12(10):2187-99
23920275
Biochem Pharmacol. 2002 Sep;64(5-6):993-8
12213597
Cancer Lett. 2016 Apr 1;373(1):36-44
26801746
Nat Rev Cancer. 2010 Apr;10(4):267-77
20300106