Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77

We have previously shown that Bcl-2 is paradoxically downregulated in paclitaxel (PTX)-resistant cancer cells. We reveal here that PTX directly targets Bcl-2 in its disordered loop domain, thereby facilitating the initiation of apoptosis. Molecular modeling revealed an extraordinary similarity between the PTX binding sites in Bcl-2 and b-tubulin, leading us to speculate that PTX could be mimetic of an endogenous peptide ligand which binds both proteins. We tested the hypothesis that PTX mimics Nur77, which, like PTX, changes the function of Bcl-2. This premise was confirmed by Nur77 interacting with both PTX targets (Bcl-2 and b-tubulin), and a peptide sequence mimicking the Nur77 structural region, thus reproducing the PTX-like effects of tubulin polymerization and opening of 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 PTX-based therapy.