Biological effects of induced MYCN hyper-expression in MYCN-amplified neuroblastomas.
Neuroblastoma is a childhood malignancy of the sympathetic nervous system. The tumor exhibits two different phenotypes: favorable and unfavorable. MYCN amplification is associated with rapid tumor progression and the worst neuroblastoma disease outcome. We have previously reported that inhibitors of histone deacetylase (HDAC) and proteasome enhance favorable neuroblastoma gene expression in neuroblastoma cell lines and inhibit growth of these cells. In this study, we investigated the effect of trichostatin A or TSA (an HDAC inhibitor), and epoxomycin (a proteasome inhibitor) on MYCN and p53 expression in MYCN-amplified neuroblastoma cells. It was found that TSA down-regulated MYCN expression, but Epoxomycin and the TSA/Epoxomycin combination led to MYCN hyper-expression in MYCN-amplified neuroblastoma cell lines. Despite their contrasting effects on MYCN expression, TSA and Epoxomycin caused growth suppression and cell death of the MYCN-amplified cell lines examined. Consistent with these data, forced hyper-expression of MYCN in MYCN-amplified IMR5 cells via transfection resulted in growth suppression and the increased expression of several genes known to suppress growth or induce cell death. Furthermore, Epoxomycin as a single agent and its combination with TSA enhance p53 expression in the MYCN-amplified neuroblastoma cell lines. Unexpectedly, co-transfection of TP53 and MYCN in IMR5 cells resulted in high p53 expression but a reduction of MYCN expression. Together our data suggest that either down regulation or hyper-expression of MYCN results in growth inhibition and/or apoptosis of MYCN-amplified neuroblastoma cells. In addition, elevated p53 expression has a suppressive effect on MYCN expression in these cells.
Torres
Jaime
J
Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Regan
Paul L
PL
Edo
Robby
R
Leonhardt
Payton
P
Jeng
Eric I
EI
Rappaport
Eric F
EF
Ikegaki
Naohiko
N
Tang
Xao X
XX
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D009842:Oligopeptides; D015513:Oncogene Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; C505407:CASP3 protein, human; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin
Genes Dev. 1998 Aug 1;12(15):2424-33
9694806
Mol Cancer Ther. 2005 May;4(5):779-86
15897242
Clin Cancer Res. 1999 Jun;5(6):1491-6
10389937
Cell Death Differ. 2007 Mar;14(3):411-21
16917513
N Engl J Med. 1985 Oct 31;313(18):1111-6
4047115
Cancer Res. 2002 Nov 1;62(21):6108-15
12414635
Genes Dev. 2000 Mar 15;14(6):704-18
10733530
Oncogene. 2001 Oct 4;20(45):6503-15
11641774
Bioinformatics. 2004 May 1;20(7):1060-5
14764574
J Biol Chem. 2000 Mar 10;275(10):7337-42
10702305
J Immunol Methods. 1989 Nov 30;124(2):205-10
2513357
Science. 1984 Jun 8;224(4653):1121-4
6719137
Mol Cell Biol. 1990 Nov;10(11):5772-81
2233717
Clin Cancer Res. 2006 Oct 1;12(19):5693-7
17020972
Science. 1999 Apr 2;284(5411):156-9
10102818
Clin Cancer Res. 2004 Sep 1;10(17):5837-44
15355914
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4407-11
7753819
Cancer Res. 2001 Jan 1;61(1):8-13
11196202
Nature. 1985 Jan 31-Feb 6;313(6001):404-6
3855502
Int J Oncol. 2009 Oct;35(4):845-50
19724921
Proc Natl Acad Sci U S A. 1986 Aug;83(16):5929-33
2426708
Oncogene. 2005 Jun 2;24(24):3875-85
15735666
Biochem Biophys Res Commun. 2006 Dec 8;351(1):192-7
17055458
Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10936-41
10984508
PLoS One. 2009 Jun 04;4(6):e5799
19495417
Oncogene. 2009 Nov 19;28(46):4041-52
19802002