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Inhibitors of Mammalian Target of Rapamycin Downregulate MYCN Protein Expression and Inhibit Neuroblastoma Growth in Vitro and in Vivo

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Inhibitors of Mammalian Target of Rapamycin Downregulate MYCN Protein Expression and Inhibit Neuroblastoma Growth in Vitro and in Vivo Oncogene (2008) 27, 2910–2922 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ORIGINAL ARTICLE Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo JI Johnsen1,6, L Segerstro¨ m1,6, A Orrego2, L Elfman1, M Henriksson3,BKa˚ gedal4, S Eksborg1, B Sveinbjo¨ rnsson1,5 and P Kogner1 1Department of Woman and Child Health, Karolinska Institutet, Childhood Cancer Research Unit, Stockholm, Sweden; 2Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; 3Department of Microbiology, Tumor and Cellbiology, Karolinska Institutet, Stockholm, Sweden; 4Division of Clinical Chemistry, Faculty of Health Sciences, Linko¨ping University, Sweden and 5Department of Cell Biology and Histology, University of Tromso¨, Tromso¨, Norway Mammalian target of rapamycin (mTOR) has been shown the most common and deadly solid tumor of childhood to play an important function in cell proliferation, (Brodeur, 2003). Amplification of the MYCN oncogene metabolism and tumorigenesis, and proteins that regulate is associated with rapid tumor progression and fre- signaling through mTOR are frequently altered in human quently detected in advanced-stage neuroblastoma, but cancers. In this study we investigated the phosphorylation is also a major negative prognostic factor in localized status of key proteins in the PI3K/AKT/mTOR pathway tumors (Schwab et al., 2003). Advanced-stage tumors and the effects of the mTOR inhibitors rapamycin and and those with MYCN amplification show typically CCI-779 on neuroblastoma tumorigenesis. Significant emergence of treatment resistance, and alternative expression of activated AKT and mTOR were detected treatment strategies for these patients are therefore in all primary neuroblastoma tissue samples investigated, urgently needed. but not in non-malignant adrenal medullas. mTOR Proteins regulating signaling through the phosphatidy- inhibitors showed antiproliferative effects on neuroblasto- linositol 3-kinase (PI3K)/AKT/mTOR pathway are fre- ma cells in vitro. Neuroblastoma cell lines expressing high quently altered in various cancers (Hennessy et al., 2005; levels of MYCN were significantly more sensitive to Cully et al., 2006). Activation of PI3K, AKT or mTOR is mTOR inhibitors compared to cell lines expressing low associated with resistance to apoptosis, increased cell MYCN levels. Established neuroblastoma tumors treated proliferation and deregulated cellular energy metabolism with mTOR inhibitors in vivo showed increased apoptosis, (Hennessy et al., 2005; Cully et al., 2006). mTOR, a serine/ decreased proliferation and inhibition of angiogenesis. threonine kinase, is a central regulator of cell growth and Importantly, mTOR inhibitors induced downregulation of proliferation by controlling protein translation, cytoskele- vascular endothelial growth factor A (VEGF-A) secretion, ton organization and energy metabolism (Hay, 2005; cyclin D1 and MYCN protein expression in vitro and Hennessy et al., 2005; Cully et al., 2006). mTOR regulates in vivo. Our data suggest that mTOR inhibitors have translation by phosphorylation of ribosomal p70S6 kinase therapeutic efficacy on aggressive MYCN amplified 1 (S6K1), thus allowing translation of ribosomal proteins, neuroblastomas. and cap-dependent translation through phosphorylation Oncogene (2008) 27, 2910–2922; doi:10.1038/sj.onc.1210938; of eukaryotic translation initiation factor 4E-binding published online 19 November 2007 protein 1 (4E-BP1) (Hay, 2005; Hennessy et al., 2005; Cully et al., 2006) Keywords: neuroblastoma; mTOR; rapamycin; CCI-779; In this study we investigated the activation status of MYCN; preclinical key protein involved in the PI3K/AKT/mTOR signaling pathway in neuroblastoma primary tumors and the effects of mTOR inhibition on neuroblastoma cell growth in vitro and in vivo. Introduction Results Neuroblastoma, an embryonic tumor derived from primitive cells of the sympathetic nervous system, is Expression of phosphorylated AKT and mTOR in primary neuroblastoma, ganglioneuroma and Correspondence: L Segerstro¨ m, Childhood Cancer Research Unit, non-malignant adrenal tissue samples Q6:05, Department of Women & Child Health, Karolinska Institutet, We investigated 30 primary neuroblastoma tissue S-171-76, Stockholm, Sweden. E-mail: [email protected] samples from different biological subsets and all clinical 6These authors contributed equally to this work. Received 4 April 2007; revised 21 September 2007; accepted 17 October stages for the expression of activated AKT and mTOR 2007; published online 19 November 2007 using antibodies directed against phosphorylated AKT mTOR inhibitors in neuroblastoma therapy JI Johnsen et al 2911 (pAKT ser473) and mTOR (pmTOR ser2448). All 30 resulting in a potent inhibition of mTOR signaling samples analysed showed specific expression of pAKT (Hennessy et al., 2005). The effect of rapamycin or CCI- and pmTOR in the cytoplasm (Table 1, Figure 1). 779 on proliferation was investigated in seven neuro- Four ganglioneuromas were investigated and showed blastoma cell lines, of which three have MYCN gene pAKT and pmTOR immunopositivity in the tumor- amplification and express MYCN protein, three are not derived ganglion cells but not in the surrounding benign MYCN amplified but express MYCN protein and one stroma (Table 1, Figure 1). Non-malignant adrenals has neither MYCN gene amplification nor expresses high from children showed weak staining for pAKT and levels of MYCN protein (Table 2; Beppu et al., 2004). All pmTOR in the cortex whereas the medulla, where the neuroblastoma cell lines demonstrated a concentration- majority of primary neuroblastoma arises, was negative dependent decrease in cell viability after 48 h of exposure (Table 1, Figure 1). Antibodies directed against full- (Figures 2a and b). Concentrations associated with 50% length AKT and mTOR were used as controls to growth inhibition (biologic EC50) ranged from 10.6 to eliminate differences in the overall expression levels of 15.2 mM (median 13.7 mM) for rapamycin and 9.5 to the proteins (Figure 1). 19.1 mM (median 12.0 mM) for CCI-779 (Table 2). Neuro- blastoma cell lines containing MYCN amplifications or expressing high levels of MYCN protein (Beppu et al., Inhibition of mTOR decrease neuroblastoma cell 2004) were significantly more sensitive to treatment with proliferation and clonogenic capacity rapamycin or CCI-779 compared to cell lines expressing Rapamycin and its ester-analog CCI-779 both form a low MYCN protein levels (rapamycin; IMR-32 vs SK-N- complex with FK506-binding protein 12 and mTOR, SH Po0.01, SK-N-DZ vs SH-SY5Y Po0.001, SH-SY5Y Table 1 Clinical features of tumors and control samples investigated for pAKT and pmTOR Sample Diaa Age Sex Stage MYCN 1p DNA High-riskc Outcome Survival PAKTd PmTORd (months) INSSb amplifications deletion Ploidy (months) (ser473) (ser2448) 1NBe 21 M 1 No No 4n No NEDf 159+ + + 2 NB 123 F 1 No No 3n No NED 131+ + + 3 NB 7 F 1 Yes Yes 2n No DODg 8++ 4 NB 13 M 1 No No No NED 41+ + + 5 NB 18 F 1 No No No NED 153+ + + 6 NB 31 M 2B No No 3n No NED 165+ + + 7 NB 33 F 2A No No 3n No NED 179+ + + 8 NB 8 F 2 No No 3n No NED 68+ + + 9 NB 110 M 2 No No 2n No NED 58+ + + 10 NB 5 F 2 No No 3n No AWDh 58+ + + 11 NB 103 F 2B No No 2n No NED 173+ + + 12 NB 6 M 3 No NDi 3n No NED 174+ + + 13 NB 12 F 3 No No 5n No NED 157+ + + 14 NB 0 M 3 No No 3n No DOCj 0++ 15 NB 79 M 3 Yes Yes 3n Yes NED 96+ + + 16 NB 43 F 3 No No 3n No NED 65+ + + 17 NB 43 F 3 No No 3n No NED 65+ + + 18 NB 35 F 4 No Yes Yes NED 57+ + + 19 NB 136 M 4 Yes Yes 2n Yes DOD 10 + + 20 NB 39 F 4 Yes Yes 2n Yes DOD 9 + + 21 NB 35 F 4 No Yes Yes NED 57+ + + 22 NB 28 M 4 Yes Yes 3n Yes NED 109+ + + k 23a NB 8 M 4M No No 3n No NED 59+ + + 23b NB 8 M 4M No No 4n/5n No NED 59+ + + 24 NB 41 F 4 No Yes 4n Yes NED 93+ + + 25 NB 22 M 4 Yes Yes Yes DOD 44 + + 26 NB 50 F 4 Yes Yes Yes DOD 18 + + 27 NB 0 M 4S No No 3n No NED 152+ + + 28 NB 10 M 4S No No 3n No NED 75+ + + 29 NB 0 M 4S No ND 4n No NED 174+ + + 30 NB 10 M 4S No No 3n No NED 75+ + + 31 GNl 145 M NED 108+ + + 32 GN 30 F AWD 92+ + + 33 GN 59 F NED 75+ + + 34 GN 137 M NED 122+ + + 35 ADRm 19 F ÀÀ 36 ADR 25 F ÀÀ 37 ADR 12 F ÀÀ aDiagnosis. bINSS, International Neuroblastoma Staging System. cPatient fulfilling clinico-biological criteria to obtain high-risk therapy. dPhosphorylated protein expression as assed by immunnohistochemistry according to Materials and methods. eNeuroblastoma. fNo evidence of disease. gDead of disease. hAlive with disease. iNot determined. jDead of surgical complications. kMultifocal primary. lGanglioneuroma. mNon- malignant adrenal gland. Oncogene mTOR inhibitors in neuroblastoma therapy JI Johnsen et al 2912 Non-malignant Neuroblastoma Ganglioneuroma adrenal pAKT (ser473) AKT pmTOR (ser2448) mTOR Figure 1 Immunohistochemistry of phosphorylated AKT(ser473), phosphorylated mTOR(ser2448), AKT and mTOR in neuroblastoma primary tumors, ganglioneuromas and non-malignant adrenals from children, showing specific staining of pAKT(ser473, top row) and pmTOR(ser2448, third row) in the cytoplasm of a neuroblastoma (sample no. 8, Table 1) and in differentiated ganglion cells of a benign ganglioneuroma (sample no 31, Table 1). Non-malignant adrenal showed weak staining of pAKT and pmTOR in the cortex but not in the medulla (sample no 36, Table 1). Staining of AKT (second row) and mTOR (bottom row) showed no differences in protein expression. vs SK-N-SH Po0.001, CCI-779; IMR-32 vs SK-N-FI significant dose-dependent inhibition of colony forma- Po0.01, SK-N-DZ vs SK-N-FI Po0.001 and SK-N-DZ tion (Po0.001; Figures 2e and f).
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