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Abstract
Amplification of MYCN is one of the strongest prognostic factors for poor outcome in neuroblastoma, the most common extra-cranial solid tumour in children. With less than 50% of such patients surviving their disease, better therapies are needed. MYC transcription factors up-regulate protein synthesis to drive cancer progression. Since inhibiting protein synthesis is detrimental to the progression of c-MYC driven cancers, targeting this process may offer therapeutic benefit for MYCN-driven neuroblastoma. ABCE1 is a MYC target gene and encodes an ATP-binding cassette protein that powers the dissociation of ribosomes into small and large subunits. This process allows translation re-initiation and continued protein synthesis to provide essential building blocks for cancer growth and metastasis. High tumour ABCE1 expression is correlated with reduced survival of neuroblastoma patients. ABCE1 is thus a putative therapeutic target in MYCN-driven neuroblastoma. Therefore, experiments were conducted to test whether targeting ABCE1-mediated translation can block neuroblastoma progression.
ABCE1 suppression by short interfering RNAs impaired the proliferation and migration of MYCN-amplified neuroblastoma cell lines. In contrast, ABCE1 knockdown did not affect these malignant characteristics in neuroblastoma or fibroblast cell lines lacking MYCN amplification. ABCE1 suppression also sensitised neuroblastoma cells to the chemotherapeutics topotecan, mafosfamide and etoposide, further supporting ABCE1 as a potential target in neuroblastoma.
Polysome profiling showed that ABCE1 knockdown in MYCN-amplified SK-N-BE(2) neuroblastoma cells reduced translation efficiency. Similar decreases in translation were observed in all other MYCN-amplified cell lines tested, but not in cell lines lacking MYCN amplification. Induction of MYCN expression in the SH-EP Tet21N neuroblastoma cell line substantially increased translation; however, ABCE1 knockdown returned translation to basal levels. Therefore, ABCE1 is required for the elevated translation driven by MYCN dysregulation.
In mice xenografted with MYCN-amplified neuroblastoma cells, ABCE1 suppression delayed tumour growth at both subcutaneous and orthotopic sites, prolonging the survival of tumour-bearing mice. This study shows that targeting ABCE1-mediated translation is a promising approach to selectively impair the progression of MYCN-amplified neuroblastoma.