Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells.
Vascular endothelial growth factor receptor-1 (VEGFR1) is expressed in cancer cell lines and tumors and, in pancreatic and colon cancer cells, activation of VEGFR1 is linked to increased tumor migration and invasiveness. Tolfenamic acid, a nonsteroidal anti-inflammatory drug, decreases Sp protein expression in Panc-1 and L3.6pl pancreatic cancer cells, and this was accompanied by decreased VEGFR1 protein and mRNA and decreased luciferase activity on cells transfected with constructs (pVEGFR1) containing VEGFR1 promoter inserts. Comparable results were obtained in pancreatic cancer cells transfected with small inhibitory RNAs for Sp1, Sp3, and Sp4 and all three proteins bound to GC-rich elements in the VEGFR1 promoter. These results show that VEGFR1 is regulated by Sp proteins and that treatment with tolfenamic acid decreases expression of this critical angiogenic factor. Moreover, in vitro studies in Panc-1 cells show that activation of VEGFR1 by VEGFB to increase mitogen-activated protein kinase 1/2 phosphorylation and cell migration on collagen-coated plates is also inhibited by tolfenamic acid. Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer.
Abdelrahim
Maen
M
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
Baker
Cheryl H
CH
Abbruzzese
James L
JL
Sheikh-Hamad
David
D
Liu
Shengxi
S
Cho
Sung Dae
SD
Yoon
Kyungsil
K
Safe
Stephen
S
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051703:Sp Transcription Factors / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D051706:Sp4 Transcription Factor / Q000378:metabolism; D014162:Transfection; D042561:Vascular Endothelial Growth Factor B / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D012333:RNA, Messenger; C497121:SP3 protein, human; C497124:SP4 protein, human; D051703:Sp Transcription Factors; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; C467485:VEGFB protein, human; D042561:Vascular Endothelial Growth Factor B; D062367:ortho-Aminobenzoates; D051705:Sp3 Transcription Factor; C009500:tolfenamic acid; D040281:Vascular Endothelial Growth Factor Receptor-1; D019950:Mitogen-Activated Protein Kinase 1