Oncotarget

Research Papers:

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma

Eric J. Rellinger, Chandrasekhar Padmanabhan, Jingbo Qiao, Brian T. Craig, Hanbing An, Jing Zhu, Hernán Correa, Alex G. Waterson, Craig W. Lindsley, R. Daniel Beauchamp and Dai H. Chung _

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Oncotarget. 2017; 8:91040-91051. https://doi.org/10.18632/oncotarget.19406

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Abstract

Eric J. Rellinger1,6, Chandrasekhar Padmanabhan1, Jingbo Qiao1,6, Brian T. Craig1,6, Hanbing An1, Jing Zhu1, Hernán Correa2, Alex G. Waterson3, Craig W. Lindsley3, R. Daniel Beauchamp1,4,5 and Dai H. Chung1,4,6

1Section of Surgical Sciences, Department of Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA

2Department of Pathology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA

3Department of Pharmacology and Vanderbilt Institute of Chemical Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA

4Department of Cancer Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA

5Department of Cell and Developmental Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA

6Department of Pediatric Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA

Correspondence to:

Dai H. Chung, email: dai.chung@vanderbilt.edu

R. Daniel Beauchamp, email: daniel.beauchamp@vanderbilt.edu

Keywords: ML327, neuroblastoma, MYCN, neural crest, epithelial-to-mesenchymal transition

Received: April 13, 2017     Accepted: July 03, 2017     Published: July 20, 2017

ABSTRACT

Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. MYCN-amplification is a feature of ~30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 (N-(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both MYCN-amplified and MYCN-single copy neuroblastoma cell lines. Moreover, ML327 blocked MYCN mRNA levels and tumor progression in established MYCN-amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation.


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