title: N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics.
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.
authors.affiliation: Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Casinelli
authors.affiliation: Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: LaRosa
authors.affiliation: Department of Pediatrics/ Division of Newborn Medicine, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Manika
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Cherok
authors.affiliation: Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pediatric Surgery, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Branca
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Edmunds
authors.affiliation: Department of Pediatrics/ Division of Medical Genetics, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics/ Division of Nephrology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Sunder
authors.initials: S
authors.lastname: Sims-Lucas
authors.affiliation: Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: Churley
authors.affiliation: Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Kelly
authors.affiliation: Department of Cell Biology/Center of Biological Imaging, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Cell Biology/Center of Biological Imaging, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Stolz
authors.affiliation: Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Graves