Journal
XENOBIOTICA
Volume 42, Issue 8, Pages 748-755Publisher
INFORMA HEALTHCARE
DOI: 10.3109/00498254.2012.662726
Keywords
ABC transporters; multidrug resistance; mitoxantrone; small interfering RNA; confocal microscopy
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Funding
- Intramural NIH HHS [ZIA AG000296-10] Funding Source: Medline
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1. The breast cancer resistance protein (BCRP), an ATP binding cassette (ABC) efflux transporter, plays a role in multiple drug resistance (MDR). Previous studies of the subcellular location of the ABC transporter P-glycoprotein indicated that this protein is expressed in nuclear membranes. This study examines the nuclear distribution of BCRP in seven human-derived glioblastoma (GBM) and astrocytoma cell lines. 2. BCRP expression was observed in the nuclear extracts of 6/7 cell lines. Using the GBM LN229 cell line as a model, nuclear BCRP protein was detected by immunoblotting and confocal laser microscopy. Importantly, nuclear BCRP staining was found in a subpopulation of tumour cells in a human brain GBM biopsy. 3. Mitoxantrone cytotoxicity in the LN229 cell line was determined with and without the BCRP inhibitor fumitremorgin C (FTC) and after downregulation of BCRP with small interfering RNA (siRNA). FTC inhibition of BCRP increased mitoxantrone cytotoxicity with a similar to 7-fold reduction in the IC50 and this effect was further potentiated in the siRNA-treated cells. 4. In conclusion, BCRP is expressed in the nuclear extracts of select GBM and astrocytoma cell lines and in a human GBM tumour biopsy. Its presence in the nucleus of cancer cells suggests new role for BCRP in MDR.
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