Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells

Patel, Nish and Chatterjee, Sabarni K. and Vrbanac, Vladimir and Chung, Ivy and Mu, Chunyao Jenny and Olsen, Rachelle R. and Waghorne, Carol and Zetter, Bruce R. (2010) Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 107 (6). pp. 2503-2508. ISSN 1091-6490, DOI

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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.

Item Type: Article
Additional Information: Patel, Nish Chatterjee, Sabarni K. Vrbanac, Vladimir Chung, Ivy Mu, Chunyao Jenny Olsen, Rachelle R. Waghorne, Carol Zetter, Bruce R.
Uncontrolled Keywords: Apoptosis; Glutathione-S-transferase Pi; Mitochondria; Plasma membrane; Protein translocation
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms azrahani halim
Date Deposited: 14 Mar 2013 02:18
Last Modified: 24 Oct 2018 04:19

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