Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells
Document Type
Article
Publication Date
1-1-2010
Abstract
Paclitaxel has emerged as a front line treatment for aggressive malignancies of the breast, lung, and ovary. Successful therapy of cancer is frequently undermined by the development of paclitaxel resistance. There is a growing need to find other therapeutic targets to facilitate treatment of drug-resistant cancers. Using a proteomics approach, elevated levels of Prohibitin1 (PHB1) and GST pi were found associated with paclitaxel resistance in discrete subcellular fractions of two drug-resistant sublines relative to their sensitive sublines. Immunofluorescence staining and fractionation studies revealed increased levels of PHB1 on the surface of resistant cell lines. Transiently silencing either PHB1 or GSTp gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTp resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTp significantly improved paclitaxel sensitivity in A549TR cells both in vitro and in vivo. Our results indicate that PHB1 is a mediator of paclitaxel resistance and that this resistance may depend on the cellular localization of the protein. We suggest PHB1 as a potential target for therapeutic strategies for the treatment of drug-resistant tumors.
Keywords
Apoptosis, Glutathione-S-transferase Pi, Mitochondria, Plasma membrane, Protein translocation
Divisions
fac_med
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
107
Issue
6
Publisher
National Academy of Sciences
Additional Information
Patel, Nish Chatterjee, Sabarni K. Vrbanac, Vladimir Chung, Ivy Mu, Chunyao Jenny Olsen, Rachelle R. Waghorne, Carol Zetter, Bruce R.