MYCN enhances P-gp/MDR1 gene expression in the human metastatic neuroblastoma IGR-N-91 model

被引:42
作者
Blanc, E
Goldschneider, D
Ferrandis, E
Barrois, M
Le Roux, G
Leonce, S
Douc-Rasy, S
Bénard, J
Raguénez, G
机构
[1] Inst Gustave Roussy, UMR 8126, Serv Genet, Dept Biol, F-94805 Villejuif, France
[2] Univ Paris Sud 11, CNRS, UMR 8126, Paris, France
[3] Inst Gustave Roussy, Inst Federat Rech, F-94805 Villejuif, France
[4] Inst Rech Int Servier, Dept Biol, Croissy sur Seine, France
关键词
D O I
10.1016/S0002-9440(10)63656-5
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Despite intensive high-dose chemotherapy and autologous hematopoietic stem cell transplantation, disseminated neuroblastoma (NB) frequently proves to be chemosensitive but not chemocurable, and more often so in NB-presenting MYCN amplification. To assess the direct relationship between the MYCN oncogene and chemoresistance acquisition during NB metastatic dissemination, we have studied MYCN and MDR1 genes using the human IGR-N-91 ectopic xenograft metastatic model. This characterized experimental in vitro model includes human neuroblasts derived from a subcutaneous primary tumor xenograft, disseminated blood cells, myocardium, and bone marrow (BM) metastatic cells. All IGR-N-91-derived neuroblasts harbor a consistent MYCN genomic content but, unlike primary tumor xenograft, BM, and myocardium, human neuroblasts elicit a concomitant increase in MYCN and MDR1 transcripts levels, consistent with chemoresistance phenotype and active P-gp. In contrast, no variation of MRP1 transcript level was associated with the metastatic process in this model. Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN-transfected SK-N-SH cells and in endogenous BM metastatic neuroblasts with an increase in the MYCN transcript level. Band-shift experiments indicate that IGR-N-91 cells enriched with the MycN transcription factor do bind to two E-box motifs localized within the MDR1 promoter. Overall, our data indicate that MYCN overexpression increment contributes to the acquired drug resistance that occurs throughout the NB metastatic process.
引用
收藏
页码:321 / 331
页数:11
相关论文
共 57 条
[1]   BINDING OF MYC PROTEINS TO CANONICAL AND NONCANONICAL DNA-SEQUENCES [J].
BLACKWELL, TK ;
HUANG, J ;
MA, A ;
KRETZNER, L ;
ALT, FW ;
EISENMAN, RN ;
WEINTRAUB, H .
MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (09) :5216-5224
[2]   CORRELATION OF MDR1 GENE-EXPRESSION WITH CHEMOTHERAPY IN NEURO-BLASTOMA [J].
BOURHIS, J ;
BENARD, J ;
HARTMANN, O ;
BOCCONGIBOD, L ;
LEMERLE, J ;
RIOU, G .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1989, 81 (18) :1401-1405
[3]  
Breit S, 2000, CANCER RES, V60, P4596
[4]  
BRODEUR GM, 1987, CANCER RES, V47, P4248
[5]  
BRODEUR GM, 1992, CANCER-AM CANCER SOC, V70, P1685, DOI 10.1002/1097-0142(19920915)70:4+<1685::AID-CNCR2820701607>3.0.CO
[6]  
2-H
[7]   MOLECULAR-BASIS FOR HETEROGENEITY IN HUMAN NEUROBLASTOMAS [J].
BRODEUR, GM .
EUROPEAN JOURNAL OF CANCER, 1995, 31A (04) :505-510
[8]   ABC transporters as phenotypic markers and functional regulators of stem cells [J].
Bunting, KD .
STEM CELLS, 2002, 20 (01) :11-20
[9]  
Bursztajn S, 2000, MOL BRAIN RES, V76, P363
[10]   P-GLYCOPROTEIN EXPRESSION AS A PREDICTOR OF THE OUTCOME OF THERAPY FOR NEUROBLASTOMA [J].
CHAN, HSL ;
HADDAD, G ;
THORNER, PS ;
DEBOER, G ;
LIN, YP ;
ONDRUSEK, N ;
YEGER, H ;
LING, V .
NEW ENGLAND JOURNAL OF MEDICINE, 1991, 325 (23) :1608-1614