N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics
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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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Mitotic catastrophe is a major mechanism of action of anticancer chemotherapeutics, reflecting increased resistance of neoplastic cells to intrinsic apoptosis.
“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].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [1009]
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1 retracted
Ciani, E., Guidi, S., Valle, G. D., Perini, G., Bartesaghi, R., & Contestabile, A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206177200 · Cited by 87 · see citing works
RetractedAnalysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Analyzing real-time PCR data by the comparative CT method
Schmittgen, T. D., & Livak, K. J. (2008) · Nature Protocols · doi:10.1038/nprot.2008.73 · Cited by 26,190 · see citing works
Siegel, R., Naishadham, D., & Jemal, A. (2013) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21166 · Cited by 11,825 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Dang, C. V. (2012) · Cell · doi:10.1016/j.cell.2012.03.003 · Cited by 3,390 · see citing works
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233 · see citing works
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy
Twig, G., Elorza, A., Molina, A. J. A., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., et al. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601963 · Cited by 3,082 · see citing works
Induction of apoptosis in fibroblasts by c-myc protein
Evan, G. I., Wyllie, A. H., Gilbert, C. S., Littlewood, T. D., Land, H., Brooks, M. W., Waters, C. M., Penn, L. Z., & Hancock, D. C. (1992) · Cell · doi:10.1016/0092-8674(92)90123-t · Cited by 2,941 · see citing works
Chen, H., Detmer, S. A., Ewald, A. J., Griffin, E. E., Fraser, S. E., & Chan, D. C. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200211046 · Cited by 2,601 · see citing works
Amplification of N- myc in Untreated Human Neuroblastomas Correlates with Advanced Disease Stage
Brodeur, G. M., Seeger, R. C., Schwab, M., VARMUS, H. E., & Bishop, J. M. (1984) · Science · doi:10.1126/science.6719137 · Cited by 2,261 · see citing works
Mitochondria: More Than Just a Powerhouse
McBride, H. M., Neuspiel, M., & Wasiak, S. (2006) · Current Biology · doi:10.1016/j.cub.2006.06.054 · Cited by 1,985 · see citing works
The International Neuroblastoma Risk Group (INRG) Classification System: An INRG Task Force Report
Cohn, S. L., Pearson, A. D. J., London, W. B., Monclair, T. F., Ambros, P. F., Brodeur, G. M., Faldum, A., Hero, B., Iehara, T., Machin, D., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.16.6785 · Cited by 1,915 · see citing works
During autophagy mitochondria elongate, are spared from degradation and sustain cell viability
Gomes, L. C., Benedetto, G. D., & Scorrano, L. (2011) · Nature Cell Biology · doi:10.1038/ncb2220 · Cited by 1,735 · see citing works
Smiley, S. T., Reers, M., Mottola-Hartshorn, C., Lin, M., Chen, A. B., Smith, T. W., Steele, G., & Chen, L. B. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.9.3671 · Cited by 1,629 · see citing works
Reflecting on 25 years with MYC
Meyer, N., & Penn, L. Z. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2231 · Cited by 1,575 · see citing works
Mitochondrial dynamics-fusion, fission, movement, and mitophagy-in neurodegenerative diseases
Chen, H., & Chan, D. C. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp326 · Cited by 1,455 · see citing works
Biedler, J. L., Helson, L., & Spengler, B. A. (1973) · PubMed · Cited by 1,295 · see citing works
Mitochondrial dynamics and apoptosis
Suen, D.-F., Norris, K. L., & Youle, R. J. (2008) · Genes & Development · doi:10.1101/gad.1658508 · Cited by 1,270 · see citing works
Metabolic regulation of mitochondrial dynamics
Mishra, P., & Chan, D. C. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201511036 · Cited by 1,096 · see citing works
Bereiter‐Hahn, J., & Vöth, M. (1994) · Microscopy Research and Technique · doi:10.1002/jemt.1070270303 · Cited by 900 · see citing works
Zhang, H., Gao, P., Fukuda, R., Kumar, G., Krishnamachary, B., Zeller, K. I., Dang, C. V., & Semenza, G. L. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.04.001 · Cited by 885 · see citing works
Transcriptional integration of mitochondrial biogenesis
Scarpulla, R. C., Vega, R. B., & Kelly, D. P. (2012) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2012.06.006 · Cited by 798 · see citing works
Chang, C., & Blackstone, C. D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c700083200 · Cited by 792 · see citing works
Mitochondrial Fission Inhibitors Suppress Endothelin-1-Induced Artery Constriction
Chen, C., Gao, J., Liu, M., Li, S., Xuan, X., Zhang, X., Zhang, X.-Y., Wei, Y., Zhen, C., Jin, J., et al. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479536 · Cited by 782 · see citing works
Transposition and amplification of oncogene-related sequences in human neuroblastomas
Kohl, N. E., Kanda, N., Schreck, R. R., Bruns, G. A. P., Latt, S. A., Gilbert, F., & Alt, F. W. (1983) · Cell · doi:10.1016/0092-8674(83)90169-1 · Cited by 729 · see citing works
Mitra, K., Wunder, C., Roysam, B., Lin, G., & Lippincott‐Schwartz, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904875106 · Cited by 625 · see citing works
Neuroblastoma: Biology, Prognosis, and Treatment
Park, J. R., Eggert, A., & Caron, H. N. (2010) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2009.11.011 · Cited by 620 · see citing works
Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis
Li, F., Wang, Y., Zeller, K. I., Potter, J. J., Wonsey, D. R., O’Donnell, K. A., Kim, J., Yustein, J. T., Lee, L. A., & Dang, C. V. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.14.6225-6234.2005 · Cited by 615 · see citing works
Self-citationMitochondrial Dysfunction in Cancer
Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00292 · Cited by 502 · see citing works
Wang, W., Wang, Y., Long, J., Wang, J., Haudek, S. B., Overbeek, P., Chang, B. H. J., Schumacker, P. T., & Danesh, F. R. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.01.009 · Cited by 476 · see citing works
Self-citationExpression and amplification of the N-myc gene in primary retinoblastoma
Lee, W., Murphree, A. L., & Benedict, W. F. (1984) · Nature · doi:10.1038/309458a0 · Cited by 453 · see citing works
SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress
Samant, S. A., Zhang, H. J., Hong, Z., Pillai, V. B., Sundaresan, N. R., Wolfgeher, D., Archer, S. L., Chan, D. C., & Gupta, M. P. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.01483-13 · Cited by 446 · see citing works
Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells
Santel, A., Frank, S., Gaume, B. R., Herrler, M., Youle, R. J., & Fuller, M. T. (2003) · Journal of Cell Science · doi:10.1242/jcs.00479 · Cited by 445 · see citing works
CaM kinase Iα–induced phosphorylation of Drp1 regulates mitochondrial morphology
Han, X.-J., Lü, Y.-F., Li, S.-A., Kaitsuka, T., Sato, Y., Tomizawa, K., Nairn, A. C., Takei, K., Matsui, H., & Matsushita, M. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200802164 · Cited by 423 · see citing works
Ambros, P. F., Ambros, I. M., Brodeur, G. M., Haber, M., Khan, J. I., Nakagawara, A., Schleiermacher, G., Speleman, F., Spitz, R. E., London, W. B., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6605014 · Cited by 403 · see citing works
The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease
Harbauer, A. B., Zahedi, R. P., Sickmann, A., Pfanner, N., & Meisinger, C. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.010 · Cited by 382 · see citing works
Stanton, B. R., Perkins, A. S., Tessarollo, L., Sassoon, D. A., & Parada, L. F. (1992) · Genes & Development · doi:10.1101/gad.6.12a.2235 · Cited by 369 · see citing works
Fzo1, a Protein Involved in Mitochondrial Fusion, Inhibits Apoptosis
Sugioka, R., Shimizu, S., & Tsujimoto, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408910200 · Cited by 341 · see citing works
Human small-cell lung cancers show amplification and expression of the N-myc gene.
Nau, M. M., Brooks, B. J., Carney, D. N., Gazdar, A. F., Battey, J. F., Sausville, E. A., & Minna, J. D. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.4.1092 · Cited by 282 · see citing works
The regulation of mitochondrial morphology: Intricate mechanisms and dynamic machinery
Palmer, C. S., Osellame, L. D., Stojanovski, D., & Ryan, M. T. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.05.021 · Cited by 280 · see citing works
MYCN regulates oncogenic MicroRNAs in neuroblastoma
Schulte, J. H., Horn, S., Otto, T., Samans, B., Heukamp, L. C., Eilers, U., Krause, M., Astrahantseff, K., Klein‐Hitpaß, L., Buettner, R., et al. (2007) · International Journal of Cancer · doi:10.1002/ijc.23153 · Cited by 267 · see citing works
Regulation of mitochondrial biogenesis and PGC-1α under cellular stress
Wenz, T. (2013) · Mitochondrion · doi:10.1016/j.mito.2013.01.006 · Cited by 258 · see citing works
Human neuroblastomas and abnormalities of chromosomes 1 and 17.
Gilbert, F., Feder, M., Balaban, G. B., Brangman, D., Lurie, D., Podolsky, R., Rinaldt, V., Vinikoor, N., & Weisband, J. (1984) · PubMed · Cited by 251 · see citing works
Activated Expression of the N- myc Gene in Human Neuroblastomas and Related Tumors
Kohl, N. E., Gee, C. E., & Alt, F. W. (1984) · Science · doi:10.1126/science.6505694 · Cited by 245 · see citing works
Buechner, J., Tømte, E., Haug, B. H., Henriksen, J. R., Løkke, C., Flægstad, T., & Einvik, C. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.220 · Cited by 201 · see citing works
Keshelava, N., Seeger, R. C., Groshen, S. G., & Reynolds, C. P. (1998) · PubMed · Cited by 187 · see citing works
Metabolic symbiosis in cancer: Refocusing the Warburg lens
Nakajima, E. C., & Houten, B. V. (2012) · Molecular Carcinogenesis · doi:10.1002/mc.21863 · Cited by 176 · see citing works
Ahuja, P., Zhao, P., Angelis, E., Ruan, H., Korge, P., Olson, A., Wang, Y., Jin, E. S., Jeffrey, F. M., Portman, M., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci38331 · Cited by 157 · see citing works
Self-citationMammalian MYC Proteins and Cancer
Tansey, W. P. (2014) · New Journal of Science · doi:10.1155/2014/757534 · Cited by 153 · see citing works
Assessing mitochondria biogenesis
Medeiros, D. M. (2008) · Methods · doi:10.1016/j.ymeth.2008.09.026 · Cited by 135 · see citing works
Mitochondrial Structure, Function and Dynamics Are Temporally Controlled by c-Myc
Graves, J. A., Wang, Y., Sims‐Lucas, S., Cherok, E., Rothermund, K. D., Branca, M. F., Elster, J. D., Beer–Stolz, D., Houten, B. V., Vockley, J. E., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037699 · Cited by 128 · see citing works
Self-citationMycN sensitizes neuroblastoma cells for drug-induced apoptosis
Fulda, S., Lutz, W., Schwab, M., & Debatin, K. (1999) · Oncogene · doi:10.1038/sj.onc.1202435 · Cited by 128 · see citing works
Cho, B., Choi, S. Y., Cho, H. M., Kim, H. J., & Sun, W. (2013) · Experimental Neurobiology · doi:10.5607/en.2013.22.3.149 · Cited by 125 · see citing works
Ryan, J., Tivnan, A., Fay, J., Bryan, K. R., Meehan, M., Creevey, L., Lynch, J., Bray, I. M., O’Meara, A., Davidoff, A. M., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.356 · Cited by 117 · see citing works
MYCN oncoprotein targets and their therapeutic potential
Bell, E., Chen, L., Liu, T., Marshall, G. M., Lunec, J., & Tweddle, D. A. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.01.015 · Cited by 104 · see citing works
New therapeutic targets for the treatment of high‐risk neuroblastoma
Wagner, L. M., & Danks, M. K. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22094 · Cited by 103 · see citing works
Ryan, J., Tivnan, A., Fay, J., Bryan, K. R., Meehan, M., Creevey, L., Lynch, J., Bray, I. M., O’Meara, A., Tracey, L., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.425 · Cited by 94 · see citing works
Regulation of Reactive Oxygen Species Homeostasis by Peroxiredoxins and c-Myc
Graves, J. A., Metukuri, M. R., Scott, D. K., Rothermund, K. D., & Prochownik, E. V. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807564200 · Cited by 89 · see citing works
Self-citationCDK5-dependent inhibitory phosphorylation of Drp1 during neuronal maturation
Cho, B., Cho, H. M., Kim, H. J., Jeong, J., Park, S. K., Hwang, E. M., Park, J., Kim, W. R., Kim, H., & Sun, W. (2014) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.36 · Cited by 84 · see citing works
Respiratory Chain Complexes in Dynamic Mitochondria Display a Patchy Distribution in Life Cells
Muster, B., Kohl, W., Wittig, I., Strecker, V., Joos, F., Haase, W., Bereiter‐Hahn, J., & Busch, K. B. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011910 · Cited by 74 · see citing works
Busch, K. B., Bereiter-Hahn, J., Wittig, I., Schägger, H., & Jendrach, M. (2006) · Molecular Membrane Biology · doi:10.1080/09687860600877292 · Cited by 64 · see citing works
A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts
Berns, K., Hijmans, E. M., Koh, E. Y., Daley, G. Q., & Bernards, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203639 · Cited by 60 · see citing works
Thiele, C. J., Deutsch, L., & Israel, M. A. (1988) · PubMed · Cited by 57 · see citing works
Myc family of cellular oncogenes
DePinho, R. A., Mitsock, L., Hatton, K. S., Ferrier, P., Zimmerman, K., Legouy, E., Tesfaye, A., Collum, R. G., Yancopoulos, G. D., Nisen, P. D., et al. (1987) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240330404 · Cited by 53 · see citing works
Micro-RNA-21 regulates the sensitivity to cisplatin in human neuroblastoma cells
Chen, Y., Tsai, Y., Yu, F., & Tseng, S. (2012) · Journal of Pediatric Surgery · doi:10.1016/j.jpedsurg.2012.05.013 · Cited by 48 · see citing works
Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission
Richter, V., Singh, A. P., Kvansakul, M., Ryan, M. T., & Osellame, L. D. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1950-y · Cited by 46 · see citing works
Mitochondrial fusion: A mechanism of cisplatin-induced resistance in neuroblastoma cells?
Santin, G., Piccolini, V. M., Barni, S., Veneroni, P., Giansanti, V., Bo, V. D., Bernocchi, G., & Bottone, M. G. (2012) · NeuroToxicology · doi:10.1016/j.neuro.2012.10.011 · Cited by 38 · see citing works
The N‐myc Proto‐oncogene: Developmental Expression and in vivo Site‐Directed Mutagenesis
Stanton, B. R., & Parada, L. F. (1991) · Brain Pathology · doi:10.1111/j.1750-3639.1991.tb00058.x · Cited by 38 · see citing works
Solovyan, V. T., Bezvenyuk, Z., Huotari, V., Tapiola, T., Suuronen, T., & Salminen, A. (1998) · Molecular Brain Research · doi:10.1016/s0169-328x(98)00234-4 · Cited by 36 · see citing works
Landay, M. F., Oster, S. K., Khosravi, F., Grove, L. E., Yin, X., Sedivy, J. M., Penn, L. Z., & Prochownik, E. V. (2000) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400701 · Cited by 36 · see citing works
Hewitt, V. L., Heinz, E., Shingú-Vázquez, M., Qu, Y., Jeličić, B., Lo, T. L., Beilharz, T. H., Dumsday, G. J., Gabriel, K., Traven, A., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206345109 · Cited by 27 · see citing works
Murphy, D. M., Buckley, P. G., Bryan, K. R., Watters, K. M., Köster, J., Sluis, P. V., Molenaar, J. J., Versteeg, R., & Stallings, R. L. (2010) · Molecular Carcinogenesis · doi:10.1002/mc.20722 · Cited by 27 · see citing works
Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung
Zhang, S. X. L., Miller, J. J., Stolz, D. B., Serpero, L. D., Zhao, W., Gozal, D., & Wang, Y. (2008) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2008-0003oc · Cited by 18 · see citing works
Self-citationHIGH-RISK NEUROBLASTOMA: A Therapy in Evolution
Fong, A. P., & Park, J. R. (2009) · Pediatric Hematology and Oncology · doi:10.3109/08880010903121173 · Cited by 15 · see citing works
Constancy in Integrated Cisplatin Plasma Concentrations Among Pediatric Patients
Goodisman, J., & Souid, A. (2006) · The Journal of Clinical Pharmacology · doi:10.1177/0091270006286793 · Cited by 14 · see citing works
Monoclonal Antibodies Against Xenopus Greatwall Kinase
Wang, L., Fisher, L. A., Wahl, J. K., & Peng, A. (2011) · Hybridoma · doi:10.1089/hyb.2011.0051 · Cited by 8 · see citing works
Flagged first, then by citations
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Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationThe MYCN Protein in Health and Disease
Ruiz-Pérez, M. V., Henley, A. B., & Arsenian‐Henriksson, M. (2017) · Genes · doi:10.3390/genes8040113 · Cited by 181 · see citing works
Mitochondrial Involvement in Cisplatin Resistance
Cocetta, V., Ragazzi, E., & Montopoli, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143384 · Cited by 140 · see citing works
“Moreover, the inhibition of mitochondrial fusion by silencing of MFN1 increases cisplatin sensitivity in human neuroblastoma cells [115].”
BackgroundRedox‐Responsive Nanoparticle‐Mediated Systemic RNAi for Effective Cancer Therapy
Xu, X., Wu, J., Liu, S., Saw, P. E., Tao, W., Li, Y., Krygsman, L., Yegnasubramanian, S., Marzo, A. M. D., Shi, J., et al. (2018) · Small · doi:10.1002/smll.201802565 · Cited by 115 · see citing works
PD-L1, inflammation, non-coding RNAs, and neuroblastoma: Immuno-oncology perspective
Nallasamy, P., Chava, S. P., Verma, S. S., Mishra, S., Gorantla, S., Coulter, D. W., Byrareddy, S. N., Batra, S. K., Gupta, S. C., & Challagundla, K. B. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.11.009 · Cited by 75 · see citing works
Mitochondria: Insights into Crucial Features to Overcome Cancer Chemoresistance
Genovese, I., Carinci, M., Modesti, L., Aguiari, G., Pinton, P., & Giorgi, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094770 · Cited by 76 · see citing works
“In addition, it has been found that the inhibition of mitochondrial fusion by silencing MFN1 increases cisplatin sensitivity in human neuroblastoma cells [70].”
BackgroundLinks between cancer metabolism and cisplatin resistance
Cocetta, V., Ragazzi, E., & Montopoli, M. (2020) · International review of cytology · doi:10.1016/bs.ircmb.2020.01.005 · Cited by 75 · see citing works
Chemotherapy Resistance: Role of Mitochondrial and Autophagic Components
Bahar, E., Han, S., Kim, J., & Yoon, H. (2022) · Cancers · doi:10.3390/cancers14061462 · Cited by 66 · see citing works
Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03087-8 · Cited by 62 · see citing works
“In cancer cells mitochondria switch to a more fused pattern [35, 36], can promote the activation of many anti-apoptotic pathways, also favoring a higher ATP production linked to the respiratory chain, thanks to an increased mitochondrial cristae density [37].”
BackgroundZou, G.-P., Yu, C., Shi, S.-L., Li, Q.-G., Wang, X.-H., Qu, X.-H., Yang, Z., Yao, W.-R., Yan, D., Jiang, L., et al. (2021) · Journal of Cancer · doi:10.7150/jca.61379 · Cited by 57 · see citing works
Seo, J. H., Agarwal, E., Chae, Y. C., Lee, Y. G., Garlick, D. S., Storaci, A. M., Ferrero, S., Gaudioso, G., Gianelli, U., Vaira, V., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.09.017 · Cited by 49 · see citing works
“In addition to oxidative phosphorylation gene expression [36] and modulation of multiple bioenergetics pathways [37], Myc-directed transcription has been associated with mitochondrial dynamics, promoting changes in organelle structure that favour therapy resistance [38] or heightened subcellular mitochondrial traffick…”
BackgroundPost-translational modifications on mitochondrial metabolic enzymes in cancer
Peng, Y., Liu, H., Liu, J., & Long, J. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.12.264 · Cited by 47 · see citing works
The Interplay between Oncogenic Signaling Networks and Mitochondrial Dynamics
Nagdas, S., & Kashatus, D. F. (2017) · Antioxidants · doi:10.3390/antiox6020033 · Cited by 43 · see citing works
“Consistent with this, the overexpression of Myc family member N-Myc leads to increased mitochondrial fusion in neuroblastoma cells [137].”
BackgroundRuiz-Pérez, M. V., Sainero‐Alcolado, L., Oliynyk, G., Matuschek, I., Balboni, N., Ubhayasekera, S. J. K. A., Snaebjornsson, M. T., Makowski, K., Aaltonen, K. E., Bexell, D., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102128 · Cited by 39 · see citing works
Targeting MYC Dependence by Metabolic Inhibitors in Cancer
Sabnis, H. S., Somasagara, R. R., & Bunting, K. D. (2017) · Genes · doi:10.3390/genes8040114 · Cited by 36 · see citing works
Mitochondrial signaling pathways and their role in cancer drug resistance
Sharma, A., Virmani, T., Kumar, G., Sharma, A., Virmani, R., Gugulothu, D. B., Singh, K., Misra, S. K., Pathak, K., Chitranshi, N., et al. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111329 · Cited by 24 · see citing works
Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries
Zhang, X., Shetty, M., Clemente, V., Linder, S. T., & Bazzaro, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094750 · Cited by 22 · see citing works
Weng, Z., Lin, J., He, J., Gao, L., Lin, S., Tsang, L. L., Zhang, H., He, X., Wang, G., Yang, X., et al. (2021) · Neuro-Oncology · doi:10.1093/neuonc/noab241 · Cited by 22 · see citing works
Divergent Roles of Mitochondria Dynamics in Pancreatic Ductal Adenocarcinoma
Carmona‐Carmona, C. A., Pozza, E. D., Ambrosini, G., Errico, A., & Dando, I. (2022) · Cancers · doi:10.3390/cancers14092155 · Cited by 21 · see citing works
“Considering that MYC is highly expressed in some cancers, such as breast cancer [68] and neuroblastoma [80], the search for inhibitors of mitochondrial fusion opens a new approach for these types of cancer as MYLS22 (OPA1 inhibitor) recently reported by Scorrano’s group [79].”
BackgroundRay, L., Pal, M. K., & Ray, R. S. (2017) · Bioactive Materials · doi:10.1016/j.bioactmat.2017.02.003 · Cited by 20 · see citing works
Targeting lipid metabolism in cancer: neuroblastoma
Agostini, M., Melino, G., Habeb, B. F., Calandria, J. M., & Bazan, N. G. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10040-8 · Cited by 19 · see citing works
“Moreover, MYCN mediates structural changes in the mitochondrial network by increasing fusion, resulting in resistance to cell death induced by cisplatin [43].”
BackgroundTargeting K-Ras and apoptosis-driven cellular transformation in cancer
Godwin, I., Anto, N. P., Bava, S. V., Babu, M. S., & Jinesh, G. G. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00457-5 · Cited by 19 · see citing works
Liskova, V., Kajsik, M., Chovancova, B., Roller, L., & Krizanova, O. (2022) · FEBS Open Bio · doi:10.1002/2211-5463.13401 · Cited by 19 · see citing works
Zhao, Z., Ren, Y., Yuan, M., Liu, G., & Sun, J. P. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07078-x · Cited by 20 · see citing works
“While MFN2-mediated fusion enhances OXPHOS respiratory efficiency in doxo-rubicin-resistant leukemia [136], N-Myc-driven fusion in neuroblastoma paradoxically elevates glycolytic ATP production alongside mitochondrial biogenesis [137].”
Seneviratne, J. A., Carter, D. R., Mittra, R., Gifford, A. J., Kim, P. Y., Luo, J., Mayoh, C., Salib, A., Rahmanto, A. S., Murray, J. E., et al. (2022) · International Journal of Cancer · doi:10.1002/ijc.34349 · Cited by 18 · see citing works
“However in NB, mitochondrial dysregulation is mediated by underlying genomic lesions,(14-16) changes in gene expression(37,38) or in response to chemotherapy.(15,39) Several mitochondria-targeted agents have shown efficacy in NB in experimental systems but have achieved only limited clinical application,(4,37) suggest…”
BackgroundAscorbate sensitizes human osteosarcoma cells to the cytostatic effects of cisplatin
Oka, N., Komuro, A., Amano, H., Dash, S., Honda, M., Ota, K., Nishimura, S., Ueda, T., Akagi, M., & Okada, H. (2020) · Pharmacology Research & Perspectives · doi:10.1002/prp2.632 · Cited by 16 · see citing works
Liu, C., Zhou, L., Chen, J., Yang, Z., Chen, S., Wang, X., Liu, X., Li, Y., Zhang, C., Wang, Y., et al. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115834 · Cited by 12 · see citing works
Self-citationChen, S., Tu, X.-Y., Xie, L., Xiong, L.-P., Song, J., & Ye, X. (2018) · Europe PMC (PubMed Central) · Cited by 11 · see citing works
Hanlon, M. B., Shohet, J. M., & Wolfe, S. A. (2025) · Nature Communications · doi:10.1038/s41467-025-60160-2 · Cited by 10 · see citing works
“Thus, Cas9 D10A treatment could potentially serve as a means of increasing the sensitivity of cancer cells harboring gene ampli fi cations to a variety of conventional therapeutics 128 – 130 .”
Tian, H., Zhang, B., Li, L., Wang, G., Li, H., & Zheng, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01692 · Cited by 10 · see citing works
“Mitochondrial elongation due to mitochondrial protein rearrangement is helpful to resist cisplatin-induced treatment in neuroblastoma cells while silencing of MFN1 inhibits mitochondrial fusion but increases cisplatin sensitivity (24).”
BackgroundMolecular regulation and therapeutic targeting of MYCN in neuroblastoma: a comprehensive review
Chen, Y., Yang, H., Xiao, L., Yan, N., & Zhang, M. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1683331 · Cited by 8 · see citing works
Yu, C., Peng, Z.-Q., Wang, T., Qu, X.-H., Yang, P. C., Huang, S.-R., Jiang, L.-P., Tou, F., & Han, X. (2023) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2023247 · Cited by 7 · see citing works
“In rat neuroblastoma B50 cells, resistance to cisplatin was found to be mediated by OPA1-mediated mitochondrial fusion [26], while inhibition of Mfn2 was shown to sensitize human neuroblastoma cells to cisplatin [27].”
BackgroundMitochondrion: Main organelle in orchestrating cancer escape from chemotherapy
Mostafavi, S., & Eskandari, N. (2023) · Cancer Reports · doi:10.1002/cnr2.1942 · Cited by 6 · see citing works
“60 Moreover, inhibition of mitophagy in breast cancer via induction of mitochondrial fission sensitized these cells to chemotherapy.”
BackgroundEfficacy of a Three Drug-Based Therapy for Neuroblastoma in Mice
Garbati, P., Barbieri, R., Calderoni, M., Baldini, F., Nizzari, M., Modesto, P., Florio, T., & Pagano, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136753 · Cited by 6 · see citing works
“Nevertheless, a high level of resistance occurs through the stable hyperactivation of oncogenes, as mycN induces the expression of multidrug resistance genes [33,34].”
BackgroundFGD5-AS1/miR-5590-3p/PINK1 induces Lenvatinib resistance in hepatocellular carcinoma
Song, M., Ma, L., Shen, C., Liu, W., Zhang, P., Bi, R., & Zhao, C. (2023) · Cellular Signalling · doi:10.1016/j.cellsig.2023.110828 · Cited by 6 · see citing works
Huang, X., Qi, L., Lu, W. D., Li, Z., Li, W., & Li, F. (2021) · Bioengineered · doi:10.1080/21655979.2021.1997697 · Cited by 5 · see citing works
“For neuroblastoma, in response to exposure of cisplatin at low dose, cells with overexpressed MYCN are revealed to be resistant to the pro - grammed cell death, which results from the increased mitochondrial fusion [34].”
RetractedMitochondrial metallopeptidase OMA1 in cancer
Purohit, G., Ghosh, P., & Khalimonchuk, O. (2024) · Advances in cancer research · doi:10.1016/bs.acr.2024.05.001 · Cited by 2 · see citing works
Farrell, A., Dall, G., Vandenberg, C. J., Shield‐Artin, K., Kyran, E. L., Blackmore, T., Lim, R., Taylor, R., Neagle, C., Ratnayake, G., et al. (2026) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03629-8 · Cited by 2 · see citing works
“Expression of N-MYC has also been associated with therapy resistance in multiple cancer types [23–25].”
Liang, S., Zhu, Y., Su, J., Luo, C., & Yang, C. (2026) · Drug Development Research · doi:10.1002/ddr.70224 · Cited by 2 · see citing works
“For example, N‐Myc influences mitochondrial dynamics by modulating the expression of multiple proteins that are associated with mitochondrial fission and fusion (Casinelli et al. 2016).”
Molecular Approach to Neuroblastoma
Bağca, B. G., & Avcı, Ç. B. (2017) · InTech eBooks · doi:10.5772/intechopen.69374 · Cited by 2 · see citing works
“MYCN plays a different criti‐ cal role in resistance to platinum compounds by inhibiting apoptosis through deregulation of PPARG coactivator 1 alpha (PPARGC1A), transcription factor A, mitochondrial (TFAM) genes regulating mitochondrial biogenesis and mitochondrial dynamin‐like GTPase (OPA1), mito‐ fusin 2 (MFN2), dyn…”
BackgroundEnergy Metabolism and Metabolic Targeting of Neuroblastoma
Aminzadeh-Gohari, S., Feichtinger, R. G., & Kofler, B. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812005-7.00007-2 · Cited by 2 · see citing works
Rahimi, S. M., & Bagheri, A. (2025) · Medical Oncology · doi:10.1007/s12032-025-03029-0 · Cited by 1 · see citing works
“Aberrant expression of N-Myc is tightly associated with tumor progression and chemoresistance [116, 117].”
Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review
Bağca, B. G., & Avcı, Ç. B. (2017) · Turkiye Klinikleri Journal of Neurology · doi:10.5336/neuro.2017-57599
Targeting mitochondrial dynamics to overcome therapeutic resistance
Chauhan, S. S., & Warfel, N. A. (2022) · The Applied Biology & Chemistry Journal · doi:10.52679/tabcj.2022.0001
Assessment of Ferroptotic Cell Death and Related Treatment Targets in Neuroblastoma
Şanlav, G., Altun, Z. S., & Olgun, N. (2024) · The Anatolian Journal of General Medical Research · doi:10.4274/anatoljmed.2023.34321
“MYCN plays a critical role in resistance to platin-based molecules by inhibiting apoptosis via deregulating PPARG coactivator 1 alpha ( PPARGC1A ) and mitochondrial transcription factor A ( TFAM ) genes (27) .”
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26733921
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26043815
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26733915
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26043677
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26733927
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26733924
Vecchio, V. D., Rehman, A., Panda, S. K., Torsiello, M., Marigliano, M., Nicoletti, M. M., Ferraro, G. A., Falco, V. D., Lappano, R., Lieto, E., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26733918
- Authors
- 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.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Graves, J Anthony
- Venue
- Cell Death Discovery
- Published
- 2016-12-12
- Volume
- 2
- Issue
- 1
- Pages
- 16082-16082
- ISSN
- 2058-7716 (ISSN-L)
- PMC
- PMC5149579
- OpenAlex
- W2565058466
- Cited by
- 52
- References
- 77
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 11 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 7
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death Discovery (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- CureSearch for Children's Cancer
- University of Pittsburgh
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK096996)
- Hyundai Hope On Wheels
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MYCN, neuroblastoma, cisplatin resistance, mitochondrial dynamics, mitochondrial fusion, mitochondrial reticulum, apoptosis resistance, bioenergetics, transcriptional regulation, post-translational regulation, MYCN amplification
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