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

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.apoptosis | glutathione-S-transferase Pi | mitochondria | plasma membrane | protein translocation

Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non-small cell lung cancer treatment

“…PHB1 is a 32-kDa protein found in organisms ranging from yeast to humans and has been implicated in aging, obesity, diabetes, cancer, and inflammatory diseases (25)(26)(27). Up-regulation of PHB1 has been reported in cancers of the stomach, esophagus, urinary bladder, breast, prostate, lung, and others (25,28), and is also associated with drug resistance (21). Nonetheless, the validity of PHB1 as a therapeutic target is not well established due to the absence of specific and effective PHB1 systemic inhibitors.…”

“…After systematic investigation and screening, this siRNA NP is successfully applied to define the role of PHB1 as a potential cancer target. Although proposed to modulate tumor cell proliferation and chemoresistance (19)(20)(21), systemic in vivo validation of PHB1 for cancer treatment remains elusive. In this work, we demonstrate antitumor activity following systemic delivery of PHB1 siRNA and propose this approach as a novel therapeutic modality for NSCLC treatment.…”

Lipid rafts: signaling and sorting platforms of cells and their roles in cancer

“…Prohibitin 1 (PHB1), a known raft component, has been found in a proteomics study to be a mediator of paclitaxel resistance [89]. This important finding has relevance for various cancers including breast, lung and ovary cancer, since PHB1 may serve as a potential target for therapeutic strategies for the treatment of drug-resistant tumors.…”

Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp

“…Taxol Tissue culture of MX-1 from Taxol-resistant MX-1 xenograft model. Tumor tissues from a Taxol-resistant MX-1 xenograft model for eight generations and a parent MX-1 xenograft model were cut into small pieces with surgical scissors and minced with sterile razor blades until the explant size was <1 mm 3 . The explants were transferred to flasks, trypsinized (Invitrogen) for 30 min, covered with complete medium and incubated in an atmosphere of 5% CO 2 and 95% air at 37˚C.…”

“…Taxane (Taxol) and docetaxel (Taxotere) are widely used in early and metastatic breast cancer as adjuvant and neoadjuvant therapies (2). Although initially responsive in breast cancer, inherent or developed Taxol resistance often limits the efficacy of Taxol (3,4). Overexpression and activity of drug efflux pumps, such as P-gp, and changes in the β-tubulin isoform mainly confer the resistance, which can be identified in the clinic.…”