The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme

Urban-Wójciuk, Zuzanna; Graham, Amy; Barker, Karen; Kwok, Colin; Sbirkov, Yordan; Howell, Louise; Campbell, James; Woster, Patrick M; Poon, Evon; Petrie, Kevin; Chesler, Louis; European Commission; Cancer Research UK; Institute of Cancer Research; Institute of Cancer Research; Institute of Cancer Research; Institute of Cancer Research; Institute of Cancer Research; Institute of Cancer Research; Medical University of South Carolina; Institute of Cancer Research; Institute of Cancer Research; Institute of Cancer Research; 0000-0002-9805-9152

The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme

2021 | 2022

Deregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor—antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen.

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المعلومات البيبليوغرافية

الناشر

Nature Publishing Group

مواضيع أخرى

Targeted therapies; Paediatric cancer

اللغة

إنجليزي

نوع الملف

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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/., http://creativecommons.org/licenses/by/4.0/

الرقم الدولي الموحد للكتاب (ردمك)

0006958088000, 0-851151752

الرقم التسلسلي المعياري الدولي (ردمد)

34522028

النوع

Journal Article; Vor - Version Of Record

في أجريس منذ: 2024-11-28

نوع الملف: Dublin Core

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تم تزويد هذا السجل من قبل University of Stirling

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