5'-Iodotubercidin represses insulinoma-associated-1 expression, decreases cAMP levels, and suppresses human neuroblastoma cell growth.
J Biol Chem
; 294(14): 5456-5465, 2019 04 05.
Article
em En
| MEDLINE
| ID: mdl-30755485
ABSTRACT
Insulinoma-associated-1 (INSM1) is a key protein functioning as a transcriptional repressor in neuroendocrine differentiation and is activated by N-Myc in human neuroblastoma (NB). INSM1 modulates the phosphoinositide 3-kinase (PI3K)-AKT Ser/Thr kinase (AKT)-glycogen synthase kinase 3ß (GSK3ß) signaling pathway through a positive-feedback loop, resulting in N-Myc stabilization. Accordingly, INSM1 has emerged as a critical player closely associated with N-Myc in facilitating NB cell growth. Here, an INSM1 promoter-driven luciferase-based screen revealed that the compound 5'-iodotubercidin suppresses adenosine kinase (ADK), an energy pathway enzyme, and also INSM1 expression and NB tumor growth. Next, we sought to dissect how the ADK pathway contributes to NB tumor cell growth in the context of INSM1 expression. We also found that 5'-iodotubercidin inhibits INSM1 expression and induces an intra- and extracellular adenosine imbalance. The adenosine imbalance, which triggers adenosine receptor-3 signaling that decreases cAMP levels and AKT phosphorylation and enhances GSK3ß activity. We further observed that GSK3ß then phosphorylates ß-catenin and promotes the cytoplasmic proteasomal degradation pathway. 5'-Iodotubercidin treatment and INSM1 inhibition suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) activity and the AKT signaling pathways required for NB cell proliferation. The 5'-iodotubercidin treatment also suppressed ß-catenin, lymphoid enhancer-binding factor 1 (LEF-1), cyclin D1, N-Myc, and INSM1 levels, ultimately leading to apoptosis via caspase-3 and p53 activation. The identification of the signaling pathways that control the proliferation of aggressive NB reported here suggests new options for combination treatments of NB patients.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Tubercidina
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Regulação Neoplásica da Expressão Gênica
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AMP Cíclico
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Proliferação de Células
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Proteínas de Neoplasias
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Neuroblastoma
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2019
Tipo de documento:
Article