Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors.

Abstract

Betulinic acid is a pentacyclic triterpene natural product initially identified as a melanoma-specific cytotoxic agent that exhibits low toxicity in animal models. Subsequent studies show that betulinic acid induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues; however, the underlying mechanism of action is unknown. Using LNCaP prostate cancer cells as a model, we now show that betulinic acid decreases expression of vascular endothelial growth (VEGF) and the antiapoptotic protein survivin. The mechanism of these betulinic acid-induced antiangiogenic and proapoptotic responses in both LNCaP cells and in tumors is due to activation of selective proteasome-dependent degradation of the transcription factors specificity protein 1 (Sp1), Sp3, and Sp4, which regulate VEGF and survivin expression. Thus, betulinic acid acts as a novel anticancer agent through targeted degradation of Sp proteins that are highly overexpressed in tumors.

• Authors: Sudhakar Chintharlapalli, Sabitha Papineni, Shashi K Ramaiah, Stephen Safe
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 6 Pg. 2816-23 (Mar 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17363604 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents, Phytogenic
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Pentacyclic Triterpenes
• SP3 protein, human
• SP4 protein, human
• Sp Transcription Factors
• Sp1 Transcription Factor
• Sp4 Transcription Factor
• Survivin
• Triterpenes
• Vascular Endothelial Growth Factor A
• Sp3 Transcription Factor
• Proteasome Endopeptidase Complex
• Betulinic Acid

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Humans
• Inhibitor of Apoptosis Proteins
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Nude
• Microtubule-Associated Proteins (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Neovascularization, Pathologic (drug therapy)
• Pentacyclic Triterpenes
• Promoter Regions, Genetic (drug effects)
• Prostatic Neoplasms (blood supply, drug therapy, metabolism, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Sp Transcription Factors (antagonists & inhibitors, metabolism)
• Sp1 Transcription Factor (antagonists & inhibitors, metabolism)
• Sp3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Sp4 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Survivin
• Triterpenes (pharmacology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays
• Betulinic Acid