Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

Brown, Iain; Shalli, Kawan; McDonald, Sarah; Moir, Susan Emma; Hutcheon, A. W.; Heys, Steven Darryll; Schofield, Andrew Craig

doi:10.1186/bcr918

Cited by 69 publications

(56 citation statements)

References 40 publications

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“…Brown et al (2004) generated MCF7 and MDA-MB-231 cell lines resistant to docetaxel, and by cDNA microarrays identified several candidates for mediating such resistance. Reduced expression of p27 was considered as a potential mechanism of resistance in their study.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular effectors of docetaxel have been related with activation of signalling pathways, such as the jun N-terminal kinase pathway (Wang and Wieder, 2004), induction of p27 protein (Brown et al, 2004;Nawrocki et al, 2004), Raf-1 kinase (Blagosklonny et al, 1996;Caraglia et al, 2005) and phosphorylation of Bcl-2 (Blagosklonny et al, 1996;Berchem et al, 1999;Wang and Wieder, 2004). It has been reported that docetaxel increases Bcl-2 phosphorylation and downregulates bcl-xl, inhibiting the antiapoptotic function of Bcl-2 family (Haldar et al, 1997;Boudny and Nakano, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

2006

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Among microtubule-targeting agents, docetaxel has received recent interest owing to its good therapeutic index. Clinical trials have underlined its potential for the treatment of advanced breast cancer, although little is known about its molecular mode of action in this context. We characterized the molecular changes induced by docetaxel in two well-known human breast carcinoma cell lines. Two mechanisms of action according to drug concentration were suggested by a biphasic sensitivity curve, and were further validated by cell morphology, cell cycle and cell death changes. Two to four nanomolar docetaxel induced aberrant mitosis followed by late necrosis, and 100 nM docetaxel induced mitotic arrest followed by apoptosis. Passing through mitosis phase was a requirement for hypodiploidy to occur, as shown by functional studies in synchronized cells and by combining docetaxel with the proteasome inhibitor MG132. Transcriptional profiling showed differences according to cell line and docetaxel concentration, with cell cycle, cell death and structural genes commonly regulated in both cell lines. Although p53 targets were mainly induced with low concentration of drug in MCF7 cells, its relevance in the dual mechanism of docetaxel cytotoxicity was ruled out by using an isogenic shp53 cell line. Many of the genes shown in this study may contribute to the dual mechanism by which docetaxel inhibits the growth of breast cancer cells at different concentrations. These findings provide a basis for rationally enhancing docetaxel therapy, considering lower concentrations, and better drug combinations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

2006

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“…Several possible mechanisms for the acquired resistance have been suggested, including altered expression of mRNA b-tubulin isotypes (Shalli et al, 2005), modulation of b-tubulin protein levels (Shalli et al, 2005), high expression of P-glycoprotein (P-gp) (Bissery et al, 1995;Liu et al, 2001), reduced expression of p27 (Brown et al, 2004) and high expression of thioredoxin . However, the mechanism is not yet completely understood.…”

Section: Introductionmentioning

confidence: 99%

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells

et al. 2007

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Docetaxel is one of the most effective chemotherapeutic agents against cancer; nevertheless, some patients develop resistance. Unfortunately, their causes and mechanisms remain unknown. We created docetaxel-resistant DRHEp2 from human laryngeal cancer HEp2 and investigated the roles of mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) on docetaxel resistance. DRHEp2 had greatly increased mtDNA content. Reduction of mtDNA content in DRHEp2 by ethidium bromide treatment reduced the resistance. These results indicate the possible roles of mtDNA-coded enzymes in mitochondrial respiratory chain (MRC) in resistant mechanisms. Oligomycin A, an Fo-ATPase inhibitor, eliminated docetaxel resistance in DRHEp2; in contrast, inhibitors of other MRC did not. RNA interference targeted to Fo-ATPase d-subunit restored docetaxelinduced cytotoxicity to DRHEp2. These results indicate the roles of Fo-ATPase for resistant mechanisms. Docetaxel induced ROS generation in HEp2 but not in DRHEp2 and antioxidant pyrrolidine dithiocarbamate eliminated docetaxel-induced cytotoxicity, suggesting roles of ROS in docetaxel-induced cell death. Furthermore, inhibition of Fo-ATPase by Oligomycin A induced docetaxel-mediated ROS generation in DRHEp2. Taken together, DRHEp2 acquired docetaxel resistance through increasing Fo-ATPase, which led to diminish docetaxelinduced ROS generation and subsequently inhibited cell death. In conclusion, mtDNA plays an important role in developing docetaxel resistance through the reduction of ROS generation by regulating Fo-ATPase.

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“…Human BC MCF-7 and MDA-MB-231 cell lines were obtained from ATCC. The parental cell line (termed docetaxel-sensitive cells) was step wide cultured and made resistant to docetaxel (termed docetaxel-resistant cells) following sequential exposure to docetaxel (SanofiAventis, Surrey, uk) at increasing concentrations as previously described (21). Cells were cultured and maintained in RPMI-1640 medium including L-glutamine, supplemented with 10% (v/v) fetal calf serum and 1% (v/v) penicillin/streptomycin (100,000 U/l penicillin, 10 mg/l streptomycin) at 37˚C in a humidified atmosphere containing 5% carbon dioxide.…”

Section: Methodsmentioning

confidence: 99%

miR-141 confers docetaxel chemoresistance of breast cancer cells via regulation of EIF4E expression

et al. 2015

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Abstract. Resistance to docetaxel, a chemotherapy drug for breast cancer (BC) treatment, occurs in ~50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through miR-141 has been proven to play an important role in cancer drug resistance. The present study investigated the role of miR-141 expression in BC cells of acquired docetaxel resistance. Inhibition of miR-141 enhanced the response to docetaxel in docetaxel-resistant cells (MCF-7/DTX and MDA-MB-231/DTX, respectively), whereas overexpression of miR-141 confered resistance in docetaxelsensitive cells (MCF-7 and MDA-MB-231, respectively). By directly targeting the eukaryotic translation initiation factor 4E (EIF4E) mRNA, miR-141 acts on genes that are necessary for drug induced apoptosis rendering the cells drug resistant. Modulation of miR-141 expression was correlated with EIF4E expression changes and a direct interaction of miR-141 with EIF4E was shown by a luciferase assay. Thus, the present study is the first to show an increased expression of miR-141 in an acquired model of docetaxel resistance in BC. This serves as a mechanism of acquired docetaxel resistance in BC cells, possibly through direct interactions with EIF4E, therefore presenting a potential therapeutic target for the treatment of docetaxel resistant BC.

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Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

Cited by 69 publications

References 40 publications

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

Molecular profiling of docetaxel cytotoxicity in breast cancer cells: uncoupling of aberrant mitosis and apoptosis

Increased mitochondrial DNA induces acquired docetaxel resistance in head and neck cancer cells

miR-141 confers docetaxel chemoresistance of breast cancer cells via regulation of EIF4E expression

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