The drug resistance-related protein LRP is the human major vault protein

Scheffer, George L.; Wijngaard, Peter; Flens, Marcel J.; Izquierdo, Miguel; Slovak, Marilyn L.; Pinedo, H.M.; Meijer, Chris J.L.M.; Clevers, Hans; Scheper, Rik J.

doi:10.1038/nm0695-578

Cited by 556 publications

(380 citation statements)

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“…Also, no detectable levels of P-glycoprotein were observed in any of the ovarian cell lines and in the SKOV3-puro and SKOV3-S2 lines (data not shown). The role of another newly described protein associated with multidrug resistance, termed the lung resistance protein (LRP or 1 10-kDa human vault protein) (Scheffer et al, 1995). was investigated in our panel of cisplatinsensitive and -resistant cell lines.…”

Section: Discussionmentioning

confidence: 99%

Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines

Sharp

Smith²,

Hobbs³

et al. 1998

Br J Cancer

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Summary The level of expression of the multidrug resistance-associated protein (MRP1) in a panel of human ovarian carcinoma cell lines and their variants with acquired cisplatin resistance was determined using Western blotting. No overexpression of MRP1 was detected in any of the cell lines. In addition, we have transfected the MRP1 gene into an intrinsically cisplatin-resistant cell line SKOV3, previously shown to have elevated levels of glutathione (GSH). The MRP1 -transfected line SKOV3-S2 was shown to be cross-resistant to doxorubicin, vincristine and etoposide but not to paclitaxel, vinblastine and platinum agents, such as cisplatin, JM216 [bis-acetato-ammine-dichloro-cyclohexylamine platinum (IV)] and AMD473 [cis-ammine dichloro (2-methyl-pyridine) platinum (II)]. No cross-resistance to any of the platinum agents was observed in a MRP1 -overexpressing human lung cancer cell line with acquired doxorubicin resistance. Reduction of GSH levels (80-90%) by buthionine sulphoximine (BSO) produced significant potentiation in cisplatin sensitivity in the parental SKOV3, the vector-alone control SKOV3-puro and the MRP1 -transfected line SKOV3-S2. The degree of sensitization was similar in all cell lines (1.6-fold). However, selective sensitization by BSO to vincristine was observed in the MRP1-transfected line (4.1-fold) but not in the vector control. No significant differences were observed in cisplatin accumulation in the SKOV3-puro and the SKOV3-S2 cells, although both these transfected lines accumulated significantly more than the parental line. Our results suggest that MRP1 does not play a significant role in platinum resistance in the human tumour cell lines investigated in this study.

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Section: Discussionmentioning

confidence: 99%

Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines

Sharp

Smith²,

Hobbs³

et al. 1998

Br J Cancer

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“…cDNA library and isolation of the LMR-12 cDNA clone Previously, a cDNA-library was derived from mRNA isolated from the human MDR fibrosarcoma cell line HT1080/DR4 (Scheffer et al, 1995). Briefly, a size-fractionated (42 kbp) oligo d(T) primed cDNA-library was constructed in the shuttle vector pCDM8 using non-self complementary BstXI adaptors (Invitrogen, Leek, The Netherlands).…”

Section: Facs Analysismentioning

confidence: 99%

“…Also, immunoprecipitation experiments did not reveal the antigen. Therefore, the expression cloning system that had succesfully been used to identify the nature of the LRP-56 Mab (Scheffer et al, 1995) was also used here. MOP8 cells were transiently transfected with pCDM8 vector, containing cDNA inserts of the MDR fibrosarcoma cell line HT1080/DR4 and screened for LMR-12 immunoreactivity.…”

Section: Frequent Lmr-12 Staining In Tumour Cell Linesmentioning

confidence: 99%

“…Immunisation of mice with the lung cancer cell line SW-1573/2R120 led to the selection of the LRP-56 Mab (Scheper et al, 1993). Expression cloning of the corresponding cDNA identified the M r 110 000 antigen as the human major vault protein (MVP) (Scheffer et al, 1995). In another endeavour using rats, we generated a panel of six Mabs reactive with proteins present at high levels in non-P-gp MDR tumour cell lines, but low or absent in the corresponding drug-sensitive, parental tumour cell lines (Flens et al, 1997).…”

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Increased expression of beta 2-microglobulin in multidrug-resistant tumour cells

et al. 2002

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The rat monoclonal antibody LMR-12 was shown earlier to react with a plasma membrane protein, upregulated in multidrugresistant cell lines. In this study, we observed distinct LMR-12 staining in 36 out of 55 non-drug-selected tumour cell lines, including melanomas, renal cell-, colon-and lung carcinomas, whereas in other tumour types, such as leukaemia and ovarian cancer, LMR-12 staining was generally low or absent. The cDNA encoding the LMR-12 antigen was isolated from a library of the multidrug-resistant human fibrosarcoma cell line HT1080/DR4 by expression cloning in MOP8 cells. Sequence analysis showed that the LMR-12 antigen is identical to the major histocompatibility complex class I molecule beta 2-microglobulin (b 2 -m). The LMR-12/ b 2 -m staining results were confirmed by mRNA microarray data from an independent National Cancer Institute study, as well as by newly obtained reverse transcriptase polymerase chain reaction data. Further analysis of the microarray data showed that b 2 -m levels closely reflected levels of major histocompatibility complex class I heavy chains and the transporter associated with antigen processing. Since the ABC transporter associated with antigen processing was previously shown to contribute to multidrug-resistance, it may very well be that the observed LMR-12/ b 2 -m levels are secondary to (elevated) levels of the transporter associated with antigen processing. A perspective arising from the present study is that drug resistant tumour cells may, by having elevated levels of major histocompatibility complex related molecules, be particular good candidates for alternative therapeutic therapies, such as cytotoxic T cell mediated immune-therapies.

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“…Recent studies have identified Human lymphocytes from the venous blood of a donor were MRP and LRP as two other drug resistance related proteins retrieved by separation on a Ficoll-Hypaque gradient involved in cellular drug transport, subcellular distribution (Histopaque 1077; Sigma Chemical, St Louis, MO, USA) The and resistance. 3,4 mononuclear cells were washed and resuspended in miniBesides immunocytochemistry which depends on the use of mum essential medium and 4% heat inactivated fetal bovine monoclonal antibodies for identification of cellular resistance serum. The lymphocytes, at a starting concentration of markers, fluorescent microscopy and confocal microscopy 1 × 10 6 /ml, were cultured in flasks containing 18 ml of cell and laser flow cytometry have been used to study transport suspension and 2 ml of 200 g/ml phytohemagglutinin-P and subcellular distribution of fluorescent drugs.…”

mentioning

confidence: 99%