N-Myc Overexpression Increases Cisplatin Resistance in Neuroblastoma Via Deregulation of Mitochondrial Dynamics

Overview

Journal Cell Death Discov

Date 2016 Dec 29

PMID 28028439

Citations 27

Authors

Gabriella Casinelli

Jeff LaRosa

Manika Sharma

Edward Cherok

Swati Banerjee

Maria Branca

Lia Edmunds

Yudong Wang

Sunder Sims-Lucas

Luke Churley

Samantha Kelly

Ming Sun

Donna Stolz

J Anthony Graves

Affiliations

Soon will be listed here.

Abstract

N-Myc is a global transcription factor that regulates the expression of genes involved in a number of essential cellular processes including: ribosome biogenesis, cell cycle and apoptosis. Upon deregulation, N-Myc can drive pathologic expression of many of these genes, which ultimately defines its oncogenic potential. Overexpression of N-Myc has been demonstrated to contribute to tumorigenesis, most notably for the pediatric tumor, neuroblastoma. Herein, we provide evidence that deregulated N-Myc alters the expression of proteins involved in mitochondrial dynamics. We found that N-Myc overexpression leads to increased fusion of the mitochondrial reticulum secondary to changes in protein expression due to aberrant transcriptional and post-translational regulation. We believe the structural changes in the mitochondrial network in response to N-Myc amplification in neuroblastoma contributes to two important aspects of tumor development and maintenance-bioenergetic alterations and apoptotic resistance. Specifically, we found that N-Myc overexpressing cells are resistant to programmed cell death in response to exposure to low doses of cisplatin, and demonstrated that this was dependent on increased mitochondrial fusion. We speculate that these changes in mitochondrial structure and function may contribute significantly to the aggressive clinical ph9enotype of N-Myc amplified neuroblastoma.

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