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Casinelli G, LaRosa J, Sharma M, et al. N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics. Cell Death Discov. 2016;2:16082doi: 10.1038/cddiscovery.2016.82.
Casinelli, G., LaRosa, J., Sharma, M., Cherok, E., Banerjee, S., Branca, M., Edmunds, L., Wang, Y., Sims-Lucas, S., Churley, L., Kelly, S., Sun, M., Stolz, D., & Graves, J. A. (2016). N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics. Cell death discovery, 216082. https://doi.org/10.1038/cddiscovery.2016.82
Casinelli, Gabriella, et al. "N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics." Cell death discovery vol. 2 (2016): 16082. doi: https://doi.org/10.1038/cddiscovery.2016.82
Casinelli G, LaRosa J, Sharma M, Cherok E, Banerjee S, Branca M, Edmunds L, Wang Y, Sims-Lucas S, Churley L, Kelly S, Sun M, Stolz D, Graves JA. N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics. Cell Death Discov. 2016 Dec 12;2:16082. doi: 10.1038/cddiscovery.2016.82. eCollection 2016. PMID: 28028439; PMCID: PMC5149579.
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Cell Death Discov. 2016 Dec 12;2:16082. doi: 10.1038/cddiscovery.2016.82. eCollection 2016.

N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics.

Cell death discovery

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

  1. Department of Pediatrics/ Division of Hematology-Oncology, University of Pittsburgh , Pittsburgh, PA, USA.
  2. Department of Pediatrics/ Division of Newborn Medicine, University of Pittsburgh , Pittsburgh, PA, USA.
  3. Department of Pediatric Surgery, University of Pittsburgh , Pittsburgh, PA, USA.
  4. Department of Microbiology and Molecular Genetics, University of Pittsburgh , Pittsburgh, PA, USA.
  5. Department of Pediatrics/ Division of Medical Genetics, University of Pittsburgh , Pittsburgh, PA, USA.
  6. Department of Pediatrics/ Division of Nephrology, University of Pittsburgh , Pittsburgh, PA, USA.
  7. Department of Cell Biology/Center of Biological Imaging, University of Pittsburgh , Pittsburgh, PA, USA.

PMID: 28028439 PMCID: PMC5149579 DOI: 10.1038/cddiscovery.2016.82

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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