Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin a correlates directly with potent antiangiogenic effects on human pancreatic cancer.

Abstract

BACKGROUND:

Human pancreatic cancer over expresses the transcription factor Sp1. However, the role of Sp1 in pancreatic cancer angiogenesis and its use as target for antiangiogenic therapy remain unexplored.

METHODS:

Archived human pancreatic cancer specimens were used to assess gene expression and microvessel density (MVD) status by immunohistochemistry: Small-interfering RNA (siRNA) was used to determine the impact of altered Sp1 expression on tumor growth and angiogenesis, and mithramycin A (MIT) was used to evaluate Sp1-targeted antiangiogenic treatment of human pancreatic cancer in animal models.

RESULTS:

The expression level of Sp1 was correlated directly with the MVD status (P < .001) and the expression level of vascular endothelial growth factor (VEGF) (P < .05). Knockdown of Sp1 expression did not affect the growth of pancreatic cancer cells in vitro but inhibited their growth and metastasis in mouse models. This antitumor activity was consistent with the in vitro and in vivo antiangiogenic activity resulting from Sp1 knockdown. Subcutaneous and intraperitoneal injection of MIT significantly suppressed the growth of human pancreatic cancer in mouse models. This tumor suppression was correlated with the suppression of Sp1 expression in growing tumors but not in normal tissues. Moreover, treatment with MIT reduced tumor MVD, which was consistent with the down-regulation of VEGF, platelet-derived growth factor, and epidermal growth factor receptor.

CONCLUSIONS:

Both clinical and experimental evidence indicated that Sp1 is a critical regulator of human pancreatic cancer angiogenesis and the antitumor activity of MIT is a result, at least in part, of the suppression of Sp1 expression and consequent down-regulation the downstream targets of Sp1 that are key to angiogenesis.

• Authors: Ping Yuan, Liwei Wang, Daoyan Wei, Jun Zhang, Zhiliang Jia, Qiang Li, Xiangdong Le, Huamin Wang, James Yao, Keping Xie
• Journal: Cancer (Cancer) Vol. 110 Issue 12 Pg. 2682-90 (Dec 15 2007) ISSN: 0008-543X [Print] United States
• PMID: 17973266 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: 2007 American Cancer Society

Chemical References

• Angiogenesis Inhibitors
• RNA, Small Interfering
• Sp1 Transcription Factor
• mithramycin A
• Plicamycin

Topics

• Adenocarcinoma (blood supply, drug therapy, metabolism)
• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Cell Line, Tumor
• Female
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Pancreatic Neoplasms (blood supply, drug therapy, metabolism)
• Plicamycin (analogs & derivatives, pharmacology, therapeutic use)
• RNA, Small Interfering (pharmacology)
• Sp1 Transcription Factor (antagonists & inhibitors, physiology)
• Xenograft Model Antitumor Assays