PMID- 23920275
OWN - NLM
STAT- MEDLINE
DCOM- 20140519
LR  - 20220330
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 12
IP  - 10
DP  - 2013 Oct
TI  - Cetuximab reverses the Warburg effect by inhibiting HIF-1-regulated LDH-A.
PG  - 2187-99
LID - 10.1158/1535-7163.MCT-12-1245 [doi]
AB  - Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer 
      metabolism toward aerobic glycolysis (i.e., the Warburg effect), which is 
      critical to supplying cancer cells with the biomass needed for proliferation. 
      Previous studies have shown that cetuximab, an EGF receptor-blocking monoclonal 
      antibody, downregulates the alpha subunit of HIF-1 (HIF-1alpha) through the 
      inhibition of EGF receptor downstream cell signaling and that downregulation of 
      HIF-1alpha is required for cetuximab-induced antiproliferative effects. However, the 
      mechanism underlying these actions has yet to be identified. In this study, we 
      used the Seahorse XF96 extracellular flux analyzer to assess the effect of 
      cetuximab treatment on changes in glycolysis and mitochondrial respiration, the 
      two major energy-producing pathways, in live cells. We found that cetuximab 
      downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in 
      cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in an 
      HIF-1alpha downregulation-dependent manner. HNSCC cells with acquired cetuximab 
      resistance expressed a high level of HIF-1alpha and were highly glycolytic. 
      Overexpression of a HIF-1alpha mutant (HIF-1alpha/DeltaODD) conferred resistance to 
      cetuximab-induced G1 phase cell-cycle arrest, which could be overcome by 
      knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced 
      the response of cetuximab-resistant cells to cetuximab. Cetuximab had no 
      noticeable inhibitory effect on glycolysis in nontransformed cells. These 
      findings provide novel mechanistic insights into cetuximab-induced cell-cycle 
      arrest from the perspective of cancer metabolism and suggest novel strategies for 
      enhancing cetuximab response.
CI  - (c)2013 AACR.
FAU - Lu, Haiquan
AU  - Lu H
AD  - Corresponding Author: Zhen Fan, Department of Experimental Therapeutics, Unit 
      1950, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, 
      Houston, TX 77030. zfan@mdanderson.org.
FAU - Li, Xinqun
AU  - Li X
FAU - Luo, Zhongguang
AU  - Luo Z
FAU - Liu, Jie
AU  - Liu J
FAU - Fan, Zhen
AU  - Fan Z
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - R01 CA129036/CA/NCI NIH HHS/United States
GR  - R21 DE021883/DE/NIDCR NIH HHS/United States
GR  - CA016672/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130806
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Biomarkers, Pharmacological)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Isoenzymes)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 1.1.1.27.- (Lactate Dehydrogenase 5)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - Antibodies, Monoclonal, Humanized/*administration & dosage
MH  - Biomarkers, Pharmacological
MH  - Carcinoma, Squamous Cell/*drug therapy/genetics/pathology
MH  - Cell Cycle Checkpoints/drug effects
MH  - Cell Line, Tumor
MH  - Cell Respiration/drug effects
MH  - Cetuximab
MH  - ErbB Receptors/antagonists & inhibitors
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Glycolysis/drug effects/genetics
MH  - Head and Neck Neoplasms/*drug therapy/genetics/pathology
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/genetics
MH  - Isoenzymes/antagonists & inhibitors/biosynthesis/genetics
MH  - L-Lactate Dehydrogenase/antagonists & inhibitors/biosynthesis/*genetics
MH  - Lactate Dehydrogenase 5
MH  - Mitochondria/drug effects
PMC - PMC3811007
MID - NIHMS514263
EDAT- 2013/08/08 06:00
MHDA- 2014/05/20 06:00
PMCR- 2014/10/01
CRDT- 2013/08/08 06:00
PHST- 2013/08/08 06:00 [entrez]
PHST- 2013/08/08 06:00 [pubmed]
PHST- 2014/05/20 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - 1535-7163.MCT-12-1245 [pii]
AID - 10.1158/1535-7163.MCT-12-1245 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2013 Oct;12(10):2187-99. doi: 10.1158/1535-7163.MCT-12-1245. 
      Epub 2013 Aug 6.