Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells
Edited by Rakesh K. Jain, Harvard Medical School, Boston, MA, and approved December 30, 2009 (received for review September 17, 2009)
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 GSTπ 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 GSTπ gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTπ resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTπ 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.
Acknowledgments
We sincerely thank Dr. John Heymach of M.D. Anderson Cancer Institute, Houston, TX, and Jeremy Force, Children’s Hospital, Boston, MA, for kindly providing us with the A549TR cells. We also thank Drs. Renata Pasqualini and Wadih Arap of M.D. Anderson Cancer Institute, Houston, TX, for providing information regarding the use of the CKGGRAKDC peptide. This work was supported by Grant CA37393 from the National Institutes of Health. N.P. was supported by a postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada.
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Published online: January 25, 2010
Published in issue: February 9, 2010
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Acknowledgments
We sincerely thank Dr. John Heymach of M.D. Anderson Cancer Institute, Houston, TX, and Jeremy Force, Children’s Hospital, Boston, MA, for kindly providing us with the A549TR cells. We also thank Drs. Renata Pasqualini and Wadih Arap of M.D. Anderson Cancer Institute, Houston, TX, for providing information regarding the use of the CKGGRAKDC peptide. This work was supported by Grant CA37393 from the National Institutes of Health. N.P. was supported by a postdoctoral fellowship from the Natural Sciences and Engineering Research Council of Canada.
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This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells, Proc. Natl. Acad. Sci. U.S.A.
107 (6) 2503-2508,
https://doi.org/10.1073/pnas.0910649107
(2010).
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