In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1956-1956
Abstract:
Neuroblastoma is the most common extracranial solid tumor in children. A key driver of high-risk neuroblastoma is the MYCN transcription factor which fuels neuroblastoma progression by enhancing metabolic processes including protein translation (1). ABCE1, a member of the ATP-binding cassette (ABC) superfamily of transporters, is a translation factor directly up-regulated by MYCN (2). It is thought to dissociate the 80S ribosome into free 40S and 60S subunits so they can re-initiate translation and provide the protein building blocks required for rapid cell growth and migration (3). High ABCE1 expression is associated with poor clinical outcome in neuroblastoma patients (2). Therefore, we hypothesized that ABCE1 suppression may inhibit the aggressiveness of neuroblastoma by disabling protein synthesis. To test this, we suppressed ABCE1 using siRNAs in MYCN-amplified neuroblastoma cell lines, SK-N-BE(2) and CHP-134, which resulted in severely impaired cell migration (P & lt;0.001) and proliferation (P & lt;0.005). In mice xenografted with SK-N-BE(2) cells, ABCE1 suppression delayed tumor growth (P=0.001) and metastasis (P & lt;0.001). Mechanistically, when polyribosome analysis was used to monitor the impact of ABCE1 expression on protein translation in SK-N-BE(2) cells, loss of ABCE1 reduced the proportion of actively translating ribosomes (P & lt;0.001), leading to lower global protein synthesis (P=0.018). This is the first report of ABCE1 acting as pro-tumorigenic factor in neuroblastoma. Our data imply that targeting the translational machinery through ABCE1 may be an effective therapeutic approach for the treatment of MYC-driven cancers. 1. Boon, K., Caron, H. N., van Asperen, R., Valentijn, L., Hermus, M. C., van Sluis, P., Roobeek, I., Weis, I., Voûte, P.A., Schwab, M. & Versteeg, R. (2001) EMBO J. 20, 1383-1393. 2. Porro, A., Haber, M., Diolaiti, D., Iraci, N., Henderson, M., Gherardi, S., Valli, E., Munoz, M.A., Xue, C., Flemming, C., Schwab, M., Wong, J.H., Marshall, G.M., Della Valle, G., Norris, M.D. & Perini, G. (2010) J. Biol. Chem. 285, 19532-19543. 3. Pisarev, A.V., Skabkin, M.A., Pisareva, V.P., Skabkina, O.V., Rakotondrafara, A.M., Hentze, M.W., Hellen C.U. & Pestova, T.V. (2010). Mol. Cell, 37, 196-210. Citation Format: Jixuan Gao, Klaartje Somers, Katherine M. Hannan, Jamie I. Fletcher, Bing Liu, Ross D. Hannan, Richard B. Pearson, Michelle Haber, Murray D. Norris, Michelle J. Henderson. ABCE1 regulates the translational profile of neuroblastoma to drive tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1956. doi:10.1158/1538-7445.AM2017-1956
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2017-1956
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2017
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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