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

2022 | 2021

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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Editeur

Nature Publishing Group

D'autres materias

Targeted therapies; Paediatric cancer

Langue

anglais

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application/pdf

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ISBN

0006958088000, 0-851151752

ISSN

34522028

Type

Journal Article; Vor - Version Of Record

Sur AGRIS depuis: 2024-11-28

Format: Dublin Core

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Cette notice bibliographique a été fournie par University of Stirling

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