Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models

Abstract

Overexpression of the transcription factor Sp1 may play a critical role in human gastric cancer angiogenesis. In the present studies, we determined whether targeting Sp1 has a therapeutic benefit. Treatment with mithramycin A (MIT) suppressed the expression of Sp1 and its downstream target genes in both human gastric cancer cell culture and tumors growing in nude mice. The molecular responses were accompanied by a significant inhibition of gastric cancer angiogenesis, growth and metastasis. Conversely, treatment with bevacizumab (BVZ), a neutralizing antibody against VEGF A, suppressed human gastric cancer growth in nude mice in a dose-dependent manner. Gene expression analyses revealed that treatment with low dose of BVZ substantially upregulated the expression of Sp1 and its downstream target genes, including VEGF and EGFR, in tumor tissues, whereas it did not have this effect on gastric cancer cells in culture. Combined treatment with BVZ and MIT produced synergistic tumor suppression, which was consistent with suppression of the expression of Sp1 and its downstream target genes. Thus, treatment with BVZ may block VEGF function but activate the pathway of its expression via positive feedback. Collectively, Sp1 is an important regulator of the expression of multiple angiogenic factors and functional status of Sp1 signaling pathway may profoundly affect the angiogenic phenotype of and effectiveness of antiangiogenic strategies for human gastric cancer.