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

Cancer Res. 2007 Mar 15;67(6):2816-23. doi: 10.1158/0008-5472.CAN-06-3735.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neovascularization, Pathologic / drug therapy
  • Pentacyclic Triterpenes
  • Promoter Regions, Genetic / drug effects
  • Prostatic Neoplasms / blood supply
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Sp Transcription Factors / antagonists & inhibitors*
  • Sp Transcription Factors / metabolism
  • Sp1 Transcription Factor / antagonists & inhibitors
  • Sp1 Transcription Factor / metabolism
  • Sp3 Transcription Factor / antagonists & inhibitors
  • Sp3 Transcription Factor / genetics
  • Sp3 Transcription Factor / metabolism
  • Sp4 Transcription Factor / antagonists & inhibitors
  • Sp4 Transcription Factor / genetics
  • Sp4 Transcription Factor / metabolism
  • Survivin
  • Triterpenes / pharmacology*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • 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
  • betulinic acid
  • Proteasome Endopeptidase Complex