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Bottom up proteomics reveals novel differentiation proteins in neuroblastoma cells treated with 13-cis retinoic acid.

ABSTRACT: Neuroblastoma, a cancer of the sympathetic nervous system, is the second most common pediatric cancer. A unique feature of neuroblastoma is remission in some patients due to spontaneous differentiation of metastatic tumors. 13-cis retinoic acid (13-cis RA) is currently used in the clinic to treat neuroblastoma due to its differentiation inducing effects. In this study, we used shotgun proteomics to identify proteins affected by 13-cis RA treatment in neuroblastoma SK-N-SH cells. Our results showed that 13-cis RA reduced proteins involved in extracellular matrix synthesis and organization and increased proteins involved in cell adhesion and neurofilament formation. These changes indicate that 13-cis RA induces tumor cell differentiation by decreasing extracellular matrix rigidity and increasing neurite overgrowth. Differentially-affected proteins identified in this study may be novel biomarkers of drug efficacy in the treatment of neuroblastoma. SIGNIFICANCE: As neuroblastoma can spontaneously differentiate, determining which proteins are involved in differentiation can guide development of novel treatments. 13-cis retinoic acid is currently used in the clinic as a differentiation inducer. Here we have established a proteome map of SK-N-SH cells treated with 13-cis retinoic acid. Bioinformatic analysis revealed the involvement of development, differentiation, extracellular matrix assembly, collagen biosynthesis, and neurofilament bundle association. This proteome map provides information as to which proteins are important for differentiation and identifies networks that can be targeted by drugs to treat neuroblastoma [1].

SUBMITTER: Halakos EG

PROVIDER: S-EPMC7079284 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Bottom up proteomics reveals novel differentiation proteins in neuroblastoma cells treated with 13-cis retinoic acid.

Halakos Effie G EG Connell Andrew J AJ Glazewski Lisa L Wei Shuo S Mason Robert W RW

Journal of proteomics 20190828

Neuroblastoma, a cancer of the sympathetic nervous system, is the second most common pediatric cancer. A unique feature of neuroblastoma is remission in some patients due to spontaneous differentiation of metastatic tumors. 13-cis retinoic acid (13-cis RA) is currently used in the clinic to treat neuroblastoma due to its differentiation inducing effects. In this study, we used shotgun proteomics to identify proteins affected by 13-cis RA treatment in neuroblastoma SK-N-SH cells. Our results show ...[more]

PMID: 31472280

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Project description:PurposeNeuroblastoma is an embryonic childhood cancer with high mortality. 13-cis retinoic acid (13-cisRA) improves survival for some patients, but many recur, suggesting clinical resistance. The mechanism of resistance and the normal differentiation pathway are poorly understood. Three-amino-acid loop extension (TALE) family genes are master regulators of differentiation. Because retinoids promote differentiation in neuroblastoma, we evaluated TALE family gene expression in neuroblastoma.Experimental designWe evaluated expression of TALE family genes in RA-sensitive and -resistant neuroblastoma cell lines, with and without 13-cisRA treatment, identifying genes whose expression correlates with retinoid sensitivity. We evaluated the roles of one gene, PBX1, in neuroblastoma cell lines, including proliferation and differentiation. We evaluated PBX1 expression in primary human neuroblastoma samples by qRT-PCR, and three independent clinical cohort microarray datasets.ResultsWe confirmed that induction of PBX1 expression, and no other TALE family genes, was associated with 13-cisRA responsiveness in neuroblastoma cell lines. Exogenous PBX1 expression in neuroblastoma cell lines, mimicking induced PBX1 expression, significantly impaired proliferation and anchorage-independent growth, and promoted RA-dependent and -independent differentiation. Reduced PBX1 protein levels produced an aggressive growth phenotype and RA resistance. PBX1 expression correlated with histologic neuroblastoma subtypes, with highest expression in benign ganglioneuromas and lowest in high-risk neuroblastomas. High PBX1 expression is prognostic of survival, including in multivariate analysis, in the three clinical cohorts.ConclusionsPBX1 is an essential regulator of differentiation in neuroblastoma and potentiates retinoid-induced differentiation. Neuroblastoma cells and tumors with low PBX1 expression have an immature phenotype with poorer prognosis, independent of other risk factors.

Dataset Information

Bottom up proteomics reveals novel differentiation proteins in neuroblastoma cells treated with 13-cis retinoic acid.

Publications

Bottom up proteomics reveals novel differentiation proteins in neuroblastoma cells treated with 13-cis retinoic acid.

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