We reported previously that Bcl-2 is paradoxically downregulated in paclitaxel-resistant cancer cells. We reveal here that paclitaxel directly targets Bcl-2 in the loop domain, thereby facilitating the initiation of apoptosis. Molecular modeling revealed an extraordinary similarity between the paclitaxel binding sites in Bcl-2 and Î²-tubulin, leading us to speculate that paclitaxel could be mimetic of an endogenous peptide ligand, which binds both proteins. We tested the hypothesis that paclitaxel mimics Nur77, which, like paclitaxel, changes the function of Bcl-2. This premise was confirmed by Nur77 interacting with both paclitaxel targets (Bcl-2 and Î²-tubulin) and a peptide sequence mimicking the Nur77 structural region, thus reproducing the paclitaxel-like effects of tubulin polymerization and opening the permeability transition pore channel in mitochondria. This discovery could help in the development of novel anticancer agents with nontaxane skeleton as well as in identifying the clinical subsets responsive to paclitaxel-based therapy. Â©2009 American Association for Cancer Research.
|Digital Object Identifier (DOI):||10.1158/0008-5472.CAN-09-0540|
|Codice identificativo ISI:||WOS:000269566000021|
|Codice identificativo Scopus:||2-s2.0-70149101801|
|Titolo:||Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77|
|Appare nelle tipologie:||1.1 Articolo in rivista|