Mitochondrial fusion: A mechanism of cisplatin-induced resistance in neuroblastoma cells?

Santin, Giada; Piccolini, Valeria Maria; Barni, Sergio; Veneroni, Paola; Giansanti, Vincenzo; Bo, Veronica Dal; Bernocchi, Graziella; Bottone, Maria Grazia

doi:10.1016/j.neuro.2012.10.011

Cited by 35 publications

(39 citation statements)

References 63 publications

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“…Previous studies suggested that increased mitochondrial fusion increased cisplatin resistance; 41 therefore, we hypothesized that the increased fusion seen in SH-N-Myc cells may be the mechanism underlying this finding. To challenge this, we transfected SH±N-Myc cells with an shRNA targeting the MFN1 gene.…”

Section: Resultsmentioning

confidence: 82%

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

Casinelli

LaRosa

Sharma

et al. 2016

Cell Death Discovery

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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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Section: Resultsmentioning

confidence: 82%

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

Casinelli

LaRosa

Sharma

et al. 2016

Cell Death Discovery

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“…It has been shown that mitochondrial stress during apoptosis not only involves cytochrome c release but also is associated with a massive remodelling of the mitochondrial ultrastructure (27,44). In healthy kidney tubular cells, mitochondria predominantly adopt a filamentous morphology (23,45), whereas, in cells undergoing apoptotic cell death, mitochondria adopt a fragmented morphology (23,45). Polymyxin B induced a concentration-and time-dependent transition of the mitochondrial morphology from filamentous (normal) to fragmented (stressed) (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…3). Mitochondrial morphology changes are associated with a loss of mitochondrial membrane potential (⌬), an indication of mitochondrial dysfunction (45). Polymyxin B also induced a concentration-dependent loss of ⌬ (Fig.…”

Section: Discussionmentioning

confidence: 96%

Major Pathways of Polymyxin-Induced Apoptosis in Rat Kidney Proximal Tubular Cells

Azad

Akter

Rogers

et al. 2015

Antimicrob Agents Chemother

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bIdentifying the pathways involved in the apoptotic cell death that is associated with polymyxin-induced nephrotoxicity is crucial for the development of strategies to ameliorate this dose-limiting side effect and for the development of novel safer polymyxins. The primary aim of this study was to identify the major pathways which lead to polymyxin-induced apoptosis in cultured rat kidney proximal tubular cells (NRK-52E). Caspase-3, -8, and -9 were activated by polymyxin B treatment in a concentrationdependent manner. Concentration-and time-dependent expression of FasL and deformation of mitochondrial morphology were revealed following polymyxin B treatment. The proportion of cells with filamentous mitochondria (regular morphology) following an 8-h treatment with 1.0 mM polymyxin B was 56.2% ؎ 9.7% (n ‫؍‬ 3). This was decreased to 30.7% ؎ 7.5% when the polymyxin B concentration was increased to 2.0 mM. The mitochondrial membrane potential (⌬ m ) decreased to 14.1% ؎ 2.9% in the cells treated with 1.0 mM polymyxin B for 24 h (n ‫؍‬ 3) compared to that in the untreated control group. Concomitantly, concentration-and time-dependent production of mitochondrial superoxide was also observed. This study is the first to have demonstrated that polymyxin-induced apoptosis is mediated through both the death receptor and mitochondrial pathways in cultured renal tubular cells. It provides key information not only for the amelioration of polymyxin-induced nephrotoxicity but also for the discovery of novel safer polymyxin-like antibiotics against Gram-negative "superbugs."

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“…For instance, there are likely to be effects of previous chemotherapeutics or targeted therapies on mitochondrial dynamics. There is some evidence showing that resistance to platinum-based therapy may arise due to mitochondrial fusion, while an enhancer of cisplatin activity may mediate its effects through increased mitochondrial fission [153,154]. Additionally, small molecule inhibitors of mitochondrial dynamics will also have effects on the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

Nagdas

Kashatus

2017

Antioxidants

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Mitochondria are dynamic organelles that alter their organization in response to a variety of cellular cues. Mitochondria are central in many biologic processes, such as cellular bioenergetics and apoptosis, and mitochondrial network morphology can contribute to those physiologic processes. Some of the biologic processes that are in part governed by mitochondria are also commonly deregulated in cancers. Furthermore, patient tumor samples from a variety of cancers have revealed that mitochondrial dynamics machinery may be deregulated in tumors. In this review, we will discuss how commonly mutated oncogenes and their downstream effector pathways regulate the mitochondrial dynamics machinery to promote changes in mitochondrial morphology as well as the physiologic consequences of altered mitochondrial morphology for tumorigenic growth.

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Mitochondrial fusion: A mechanism of cisplatin-induced resistance in neuroblastoma cells?

Cited by 35 publications

References 63 publications

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

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

Major Pathways of Polymyxin-Induced Apoptosis in Rat Kidney Proximal Tubular Cells

The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics

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