PMID- 16540671
OWN - NLM
STAT- MEDLINE
DCOM- 20060503
LR  - 20181201
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 6
DP  - 2006 Mar 15
TI  - EGFR tyrosine kinase inhibitors decrease VEGF expression by both 
      hypoxia-inducible factor (HIF)-1-independent and HIF-1-dependent mechanisms.
PG  - 3197-204
AB  - Epidermal growth factor receptor (EGFR) inhibitors can decrease vascular 
      endothelial growth factor (VEGF) expression and tumor angiogenesis. In the 
      current study, we investigate the molecular pathways by which this occurs using 
      two drugs that have been used in the clinic, gefitinib (Iressa) and erlotinib 
      (Tarceva). The decrease in VEGF expression by gefitinib in SQ20B squamous cell 
      carcinoma cells was opposed by adenoviral expression of Akt in these cells. The 
      hypoxia-inducible factor-1 (HIF-1) binding site located at approximately -1 kbp 
      in the VEGF promoter was not required for down-regulation of promoter activity by 
      gefitinib under normoxia. Furthermore, the drug decreased activity of a reporter 
      containing the -88/+54 region. In a gel shift assay, gefitinib led to decreased 
      retardation of a labeled DNA oligonucleotide probe corresponding to the -88/-66 
      region of the VEGF promoter, which contains Sp1 binding sites. These effects of 
      gefitinib on VEGF promoter activity and DNA binding were both reversed by Akt 
      expression. Phosphorylation of Sp1 was decreased in the presence of gefitinib. 
      Gefitinib also decreases VEGF expression by decreasing HIF-1alpha expression. 
      This occurs due to decreased protein translation without any change in the level 
      of HIF-1alpha mRNA. Together, these results suggest that gefitinib decreases VEGF 
      expression both by decreasing Sp1 binding to the proximal core VEGF promoter and 
      by down-regulating HIF-1alpha expression. Similar results were obtained with 
      erlotinib in SQ20B and gefitinib in HSC3 squamous carcinoma cells. These results 
      indicate that there are at least two separate mechanisms by which EGFR inhibitors 
      decrease VEGF expression.
FAU - Pore, Nabendu
AU  - Pore N
AD  - Department of Radiation Oncology, University of Pennsylvania School of Medicine, 
      Philadelphia, Pennsylvania 19104, USA.
FAU - Jiang, Zibin
AU  - Jiang Z
FAU - Gupta, Anjali
AU  - Gupta A
FAU - Cerniglia, George
AU  - Cerniglia G
FAU - Kao, Gary D
AU  - Kao GD
FAU - Maity, Amit
AU  - Maity A
LA  - eng
GR  - R01 CA093638-01/CA/NCI NIH HHS/United States
GR  - R01 CA107956-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (Sp1 Transcription Factor)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Binding Sites
MH  - Carcinoma, Squamous Cell/drug therapy/enzymology/*metabolism
MH  - Cell Line, Tumor
MH  - Down-Regulation/drug effects
MH  - Epidermal Growth Factor/antagonists & inhibitors
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Erlotinib Hydrochloride
MH  - Gefitinib
MH  - Head and Neck Neoplasms/drug therapy/enzymology/*metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Quinazolines/pharmacology
MH  - Sp1 Transcription Factor/metabolism
MH  - Vascular Endothelial Growth Factor A/antagonists & 
      inhibitors/*biosynthesis/genetics
EDAT- 2006/03/17 09:00
MHDA- 2006/05/04 09:00
CRDT- 2006/03/17 09:00
PHST- 2006/03/17 09:00 [pubmed]
PHST- 2006/05/04 09:00 [medline]
PHST- 2006/03/17 09:00 [entrez]
AID - 66/6/3197 [pii]
AID - 10.1158/0008-5472.CAN-05-3090 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Mar 15;66(6):3197-204. doi: 10.1158/0008-5472.CAN-05-3090.