Paclitaxel is widely used in the medical treatment of solid tumors. Despite the clinical success still now the exact mechanism(s) through which the drug kills cancer cells are unknown. In this work we provide evidence, through Surface Plasmon Resonance technology, that paclitaxel beside to microtubules is able also to target mitochondria by directly interacting with the disordered loop of Bcl‐2, thereby stimulating the opening of the permeability transition pore channel and ultimately reverting Bcl‐2 function from antiapoptotic to proapoptotic. Studying the paclitaxel binding site in Bcl‐2, we discovered through molecular modeling that it is positioned in the disordered loop domain and is extraordinarily similar to that experimentally defined in beta‐tubulin, thereby prompting us to speculate that paclitaxel is a peptidomimetic factor. Since to our knowledge, the only factor able to revert the Bcl‐2 function from protector to cell killer is Nur77, we tested the hypothesis that paclitaxel mimics the activity of Nur77. To address this issue, coimmunoprecipitation experiments demonstrated that like paclitaxel Nur77 interacts with Bcl‐2 in the disordered loop domain and with beta‐tubulin. Moreover, stably transformed cells with Nur77 show the classical slow band isoform of Bcl‐2 detectable in cells treated with paclitaxel. Finally, interaction between Nur‐77 and Bcl‐2 was inhibited by paclitaxel, thus demonstrating that the drug and Nur77 compete for the binding to Bcl‐2. The discovery of the molecular component mimicked by paclitaxel could promote the development of novel agonists of the paclitaxel receptor with a nontaxane structure.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C231.
- Copyright © 2009, American Association for Cancer Research