Novel Drugs that Target ErbB2
Abstract
Betulinic acid (BA) is a triterpenoid anticancer agent, and treatment of epidermal growth factor 2 (EGFR2, HER2/ErbB2)- overexpressing BT474 and MDA-MB-453 cells with 1-10 micrometers BA inhibited cell growth and induced apoptosis. BA also induced proteasome-independent downregulation of specificity protein (Sp) transcription factors Sp1, Sp3, Sp4 and survivin, a Sp-regulated gene, and decreased expression of ErbB2, ErbB2-regulated kinases and YY1, a transcription factor that regulates ErbB2 expression. Knockdown of Sp1, Sp3, Sp4 and their combination by RNA interference was accompanied by decreased expression of ErbB2, YY1 and luciferase activity in cells transfected with a construct containing the GC-rich YY1 promoter linked to a luciferase reporter gene. BA-dependent repression of Sp1, Sp3, Sp4 and Sp regulated genes was due, in part, to induction of the Sp repressor ZBTB10 and downregulation of microRNA-27a (miR-27a) which constitutively inhibits ZBTB10 expression. The effects of BA on the miR-27a:zBTB10-Sp transcription factor axis were inhibited in cells cotreated with the cannabinoid 1 (CB1) and CB2 receptor antagonists AM251 and AM630, respectively. However, in vitro binding studies with <=10 micrometers BA and a radiolabled cannabinoid did not indicate competitive binding of BA to the CB1 and CB2 receptors, suggesting a possible role for other CB-like G protein-coupled receptors.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2011
- Accession Number
- ADA547599
Entities
People
- Stephen Safe
Organizations
- Texas A&M University