Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells.
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 GSTpi 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 GSTpi gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTpi resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTpi 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.
Vascular Biology Program, Children's Hospital Boston, Boston, MA 02115, USA.
Nish
N
Patel
Sabarni K
SK
Chatterjee
Vladimir
V
Vrbanac
Ivy
I
Chung
Chunyao Jenny
CJ
Mu
Rachelle R
RR
Olsen
Carol
C
Waghorne
Bruce R
BR
Zetter
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D000091402:Prohibitins; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D017239:Paclitaxel