Suppression of ABCE1-Mediated mRNA Translation Limits N-MYC-Driven Cancer Progression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-09, Vol.80 (17), p.3706-3718
• Main Authors: Gao, Jixuan, Jung, MoonSun, Mayoh, Chelsea, Venkat, Pooja, Hannan, Katherine M, Fletcher, Jamie I, Kamili, Alvin, Gifford, Andrew J, Kusnadi, Eric P, Pearson, Richard B, Hannan, Ross D, Haber, Michelle, Norris, Murray D, Somers, Klaartje, Henderson, Michelle J
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Disease Progression; Gene Expression Regulation, Neoplastic - genetics; Heterografts; Humans; Mice; Mice, Nude; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; Neuroblastoma - genetics; Neuroblastoma - pathology; Protein Biosynthesis; RNA, Messenger
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-19-3914

The ability of the N-MYC transcription factor to drive cancer progression is well demonstrated in neuroblastoma, the most common extracranial pediatric solid tumor, where amplification heralds a poor prognosis, with only 11% of high-risk patients surviving past 5 years. However, decades of attempts of direct inhibition of N-MYC or its paralogues has led to the conclusion that this protein is "undruggable." Therefore, targeting pathways upregulated by N-MYC signaling presents an alternative therapeutic approach. Here, we show that -amplified neuroblastomas are characterized by elevated rates of protein synthesis and that high expression of ABCE1, a translation factor directly upregulated by N-MYC, is itself a strong predictor of poor clinical outcome. Despite the potent ability of N-MYC in heightening protein synthesis and malignant characteristics in cancer cells, suppression of ABCE1 alone selectively negated this effect, returning the rate of translation to baseline levels and significantly reducing the growth, motility, and invasiveness of -amplified neuroblastoma cells and patient-derived xenograft tumors . The growth of nonmalignant cells or nonamplified neuroblastoma cells remained unaffected by reduced ABCE1, supporting a therapeutic window associated with targeting ABCE1. Neuroblastoma cells with c-MYC overexpression also required ABCE1 to maintain cell proliferation and translation. Taken together, ABCE1-mediated translation constitutes a critical process in the progression of N-MYC-driven and c-MYC-driven cancers that warrants investigations into methods of its therapeutic inhibition. SIGNIFICANCE: These findings demonstrate that N-MYC-driven cancers are reliant on elevated rates of protein synthesis driven by heightened expression of ABCE1, a vulnerability that can be exploited through suppression of ABCE1.