Sp1 decoy transfected to carcinoma cells suppresses the expression of vascular endothelial growth factor, transforming growth factor beta1, and tissue factor and also cell growth and invasion activities.
Vasculature development is thought to be an important aspect in the growth and metastasis of solid tumors. Among the angiogenic factors produced by tumor cells, vascular endothelial growth factor is considered to be the most potent and pathologically important. The synthesis of this growth factor has been shown to be modulated through Sp1 function following stimulation by tumor necrosis factor alpha (TNF-alpha). Oligodeoxynucleotides (ODNs) were synthesized with either the consensus sequence for Sp1 binding (Sp1 decoy ODNs) or a mutated form of this sequence (mt-Sp1 decoy ODNs). Using the hemagglutinating virus of Japan (HVJ)-liposome method, we transferred these ODNs into cultured cancer cells (A549 and U251 cells). The TNF-alpha-mediated expression of both VEGF and transforming growth factor beta1 and tissue factor (TF) by the cancer cells could be simultaneously suppressed to less than 30% by transfection of Sp1 decoy ODNs but not by mt-Sp1 decoy ODNs. In addition, in vitro invasiveness, synthesis of mRNA for urokinase-type plasminogen activator, and cell proliferation of both cell lines were also inhibited to 40% by the transfection of only Sp1 decoy ODNs. These results suggested that the Sp1 decoy strategy would be effective for regulating tumor growth by simultaneously reducing cancer cell (a) angiogenic growth factor expression, (b) proliferation, and (c) invasiveness.
Ishibashi
H
H
Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakagawa
K
K
Onimaru
M
M
Castellanous
E J
EJ
Kaneda
Y
Y
Nakashima
Y
Y
Shirasuna
K
K
Sueishi
K
K
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002455:Cell Division / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018108:Respirovirus / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics*; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005456:Fluorescent Dyes; D008081:Liposomes; D008222:Lymphokines; D009841:Oligonucleotides; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013925:Thromboplastin; D016650:Fluorescein-5-isothiocyanate