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.

The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

“…These findings suggest that although expression of both the fusion and fission machinery is induced by Myc, it also regulates the activity levels of the machinery to tip the balance towards fusion. Consistent with this, the overexpression of Myc family member N-Myc leads to increased mitochondrial fusion in neuroblastoma cells [137]. Forcing fission in the context of inducible c-Myc expression results in decreased ATP production, suggesting that Myc-regulated fusion helps maintain proper cellular bioenergetics and ATP levels [138].…”

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

“…Importantly, the abrogation of mitotic catastrophe is a key event during neoplastic transformation and progression, mainly as it allows for the generation and/or survival of polyploid and aneuploid cells [ 975 ], whereas cancer (stem) cells reportedly display increased sensitivity to mitotic defects [ 1003 ]. However, mitotic catastrophe appears to constitute a major mechanism of action of anticancer chemotherapeutics, mostly reflecting the increased resistance of neoplastic cells to the induction of intrinsic apoptosis [ 1004 – 1009 ]. Moreover, recent data indicate that cancer cells escaping mitotic catastrophe efficiently promote the secretion of type I IFN following the detection of cytosolic dsDNA by cGAS, potentially resulting in their elimination by immunological mechanisms [ 905 , 906 ].…”

Synergism of co-delivered nanosized antioxidants displayed enhanced anticancer efficacy in human colon cancer cell lines

“…After treatment, cells were incubated with 5 μM JC-1 (ENZO life sciences) stain for 30 min at 37 °C, washed and images were visualized by fluorescence microscope [59] (Nikon Eclipse 80i equipped with Nikon DS-Ri1 12.7 megapixel camera, Japan). Fluorescent intensity per cell in four image frames for each group was quantified using NIH ImageJ analysis software (USA) by following reports [60] , [61] , [62] , [63] . Mitochondrial depolarization in each group was quantified by calculating the ratio of red to green fluorescent intensity and was normalized to the control (red-to-green fluorescent ratio of control considered as 1) [62] , [63] , [64] .…”