Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors.
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.
Chintharlapalli
Sudhakar
S
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77843-4466, USA.
Papineni
Sabitha
S
Ramaiah
Shashi K
SK
Safe
Stephen
S
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D053978:Pentacyclic Triterpenes; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051703:Sp Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051706:Sp4 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D014315:Triterpenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000094062:Betulinic Acid
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D053978:Pentacyclic Triterpenes; C497121:SP3 protein, human; C497124:SP4 protein, human; D051703:Sp Transcription Factors; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; D000077022:Survivin; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D051705:Sp3 Transcription Factor; D046988:Proteasome Endopeptidase Complex; D000094062:Betulinic Acid