Retinoic acid inhibits the cytoproliferative response to weak 50-Hz magnetic fields in neuroblastoma cells

We previously reported that intermittent exposure to a 50-Hz magnetic field (MF) at 100 μT stimulates cell proliferation in the human neuroblastoma cell line NB69. The present study aimed to investigate whether the magnetic field-induced growth promotion also occurs at a lower magnetic flux density of 10 μT. To this purpose, NB69 cells were subjected for 42 h to intermittent exposure, 3 h on/3 h off, to a 50-Hz MF at a 10 or 100 μT magnetic flux density. The field exposure took place either in the presence or in the absence of the antiproliferative agent retinoic acid. At the end of the treatment and/or incubation period, the cell growth was estimated by hemocytometric counting and spectrophotometric analysis of total protein and DNA contents. Potential changes in DNA synthesis were also assessed through proliferating cell nuclear antigen (PCNA) immunolabeling. The results confirmed previously reported data that a 42-h exposure to a 50-Hz sine wave MF at 100 μT promotes cell growth in the NB69 cell line, and showed that 10 μT induces a similar proliferative response. This effect, which was significantly associated and linearly correlated with PCNA expression, was abolished by the presence of retinoic acid in the culture medium.

[1]  Jian Wen,et al.  The effect of 100 Hz magnetic field combined with X‐ray on hepatoma‐implanted mice , 2011, Bioelectromagnetics.

[2]  Yu Weng,et al.  Effects of ELF magnetic fields on protein expression profile of human breast cancer cell MCF7 , 2005, Science in China Series C: Life Sciences.

[3]  C. Chu,et al.  Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress , 2008, Autophagy.

[4]  S. Monarca,et al.  Genotoxic effects of extremely low frequency (ELF) magnetic fields (MF) evaluated by the Tradescantia‐micronucleus assay , 2005, Environmental toxicology.

[5]  Myrtill Simkó,et al.  Gene expression analysis of ELF-MF exposed human monocytes indicating the involvement of the alternative activation pathway. , 2006, Biochimica et biophysica acta.

[6]  A. Sannino,et al.  Evaluation of Genotoxic Effects in Human Fibroblasts after Intermittent Exposure to 50 Hz Electromagnetic Fields: A Confirmatory Study , 2005, Radiation research.

[7]  Y. Jeng,et al.  Nuclear GRP75 Binds Retinoic Acid Receptors to Promote Neuronal Differentiation of Neuroblastoma , 2011, PloS one.

[8]  A. Torsello,et al.  Effects of 50 Hz electromagnetic fields on voltage-gated Ca2+ channels and their role in modulation of neuroendocrine cell proliferation and death. , 2004, Cell calcium.

[9]  Robert Winker,et al.  Chromosomal damage in human diploid fibroblasts by intermittent exposure to extremely low-frequency electromagnetic fields. , 2005, Mutation research.

[10]  G. Lovisolo,et al.  Effects of 50 Hz electromagnetic field exposure on apoptosis and differentiation in a neuroblastoma cell line , 2003, Bioelectromagnetics.

[11]  R. Kannagi,et al.  Role of down-regulated neutral ceramidase during all-trans retinoic acid-induced neuronal differentiation in SH-SY5Y neuroblastoma cells. , 2012, Journal of biochemistry.

[12]  C. Dekker,et al.  Direct measurement of electrical transport through DNA molecules , 2000, Nature.

[13]  Jukka Juutilainen,et al.  Do electromagnetic fields enhance the effects of environmental carcinogens? , 2008, Radiation protection dosimetry.

[14]  W. Soichi,et al.  Guidelines for limiting exposure to electric fields induced by movement of the human body in a static magnetic field and by time-varying magnetic fields below 1 Hz. , 2014, Health physics.

[15]  L. Malkas,et al.  Small-Molecule Targeting of Proliferating Cell Nuclear Antigen Chromatin Association Inhibits Tumor Cell Growth , 2012, Molecular Pharmacology.

[16]  Ferdinando Bersani,et al.  Synergic effect of retinoic acid and extremely low frequency magnetic field exposure on human neuroblastoma cell line BE(2)C , 2010, Bioelectromagnetics.

[17]  R. Adair Extremely low frequency electromagnetic fields do not interact directly with DNA. , 1998, Bioelectromagnetics.

[18]  M. Imamura,et al.  All-trans retinoic acid induces differentiation of ducts and endocrine cells by mesenchymal/epithelial interactions in embryonic pancreas. , 2003, Diabetes.

[19]  T. Helleday,et al.  PCNA on the crossroad of cancer. , 2009, Biochemical Society transactions.

[20]  M. M. Bradford A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[21]  S. Grimaldi,et al.  50 Hz Extremely Low Frequency Electromagnetic Fields Enhance Protein Carbonyl Groups Content in Cancer Cells: Effects on Proteasomal Systems , 2009, Journal of biomedicine & biotechnology.

[22]  Jae-Seon Lee,et al.  Extremely low frequency magnetic fields do not elicit oxidative stress in MCF10A cells. , 2012, Journal of radiation research.

[23]  R. Alessandro,et al.  Extremely low frequency electromagnetic fields (ELF‐EMFs) induce in vitro angiogenesis process in human endothelial cells , 2008, Bioelectromagnetics.

[24]  Matthew C. Tuthill,et al.  Retinoic acid induced downregulation of MYCN is not mediated through changes in Sp1/Sp3 , 2008, Pediatric blood & cancer.

[25]  M. Trillo,et al.  Influence of a 50 Hz magnetic field and of all-trans‑retinol on the proliferation of human cancer cell lines. , 2012, International journal of oncology.

[26]  A. Boninsegna,et al.  50-Hz extremely low frequency electromagnetic fields enhance cell proliferation and DNA damage: possible involvement of a redox mechanism. , 2005, Biochimica et biophysica acta.

[27]  K. Burton A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. , 1956, The Biochemical journal.

[28]  H. Rüdiger,et al.  Cell type-specific genotoxic effects of intermittent extremely low-frequency electromagnetic fields. , 2005, Mutation research.

[29]  Martin Dugas,et al.  Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia , 2012, Nature Medicine.

[30]  M. Gessler,et al.  Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro , 2011, Molecular Cancer.

[31]  M. Marzinke,et al.  The all-trans retinoic acid (atRA)-regulated gene Calmin (Clmn) regulates cell cycle exit and neurite outgrowth in murine neuroblastoma (Neuro2a) cells. , 2012, Experimental cell research.

[32]  C. di Ilio,et al.  Fifty hertz extremely low-frequency electromagnetic field causes changes in redox and differentiative status in neuroblastoma cells. , 2007, The international journal of biochemistry & cell biology.

[33]  M Simkó,et al.  Micronucleus formation in human amnion cells after exposure to 50 Hz MF applied horizontally and vertically. , 1998, Mutation research.

[34]  Jan Koster,et al.  NF1 Is a Tumor Suppressor in Neuroblastoma that Determines Retinoic Acid Response and Disease Outcome , 2010, Cell.

[35]  Rony Seger,et al.  Mechanism of short-term ERK activation by electromagnetic fields at mobile phone frequencies. , 2007, The Biochemical journal.

[36]  国際非電離放射線防護委員会 ICNIRP statement on the "Guidelines for limiting exposure to time-varying electric, magnetic, and electromagnetic fields (up to 300 GHz)". , 2009, Health physics.

[37]  M. Gerbase,et al.  Phosphorylated Extracellular Signal-regulated Kinases Are Significantly Increased in Malignant Mesothelioma , 2006, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[38]  Leeka Kheifets,et al.  Occupational electric and magnetic field exposure and brain cancer: a meta-analysis. , 1995 .

[39]  Peter K. T. Pang,et al.  The establishment of a reliable cytotoxic system with SK-N-SH neuroblastoma cell culture , 2003, Journal of Neuroscience Methods.

[40]  J. Podd,et al.  Elevated sister chromatid exchange frequencies in dividing human peripheral blood lymphocytes exposed to 50 Hz magnetic fields , 2007, Bioelectromagnetics.

[41]  M. Trillo,et al.  The Proliferative Response of NB69 Human Neuroblastoma Cells to a 50 Hz Magnetic Field is mediated by ERK1/2 Signaling , 2012, Cellular Physiology and Biochemistry.

[42]  J. Contessa,et al.  ERBB receptor tyrosine kinases and cellular radiation responses , 2003, Oncogene.

[43]  K. Matthay,et al.  Retinoid therapy of high-risk neuroblastoma. , 2003, Cancer letters.

[44]  C. di Ilio,et al.  Molecular basis underlying the biological effects elicited by extremely low‐frequency magnetic field (ELF‐MF) on neuroblastoma cells , 2011, Journal of cellular biochemistry.

[45]  C. Johansen,et al.  Neurodegenerative Diseases in Welders and Other Workers Exposed to High Levels of Magnetic Fields , 2003, Epidemiology.

[46]  M. Mazzanti,et al.  Calcium protects differentiating neuroblastoma cells during 50 Hz electromagnetic radiation. , 2001, Biophysical journal.

[47]  L. Larsson,et al.  Combined IFN-γ and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells , 2007, Molecular Cancer Therapeutics.

[48]  Alexander Pilger,et al.  Induction of DNA strand breaks by intermittent exposure to extremely-low-frequency electromagnetic fields in human diploid fibroblasts. , 2002, Mutation research.

[49]  M. Skonieczna,et al.  Short‐term exposure to 50 Hz ELF‐EMF alters the cisplatin‐induced oxidative response in AT478 murine squamous cell carcinoma cells , 2012, Bioelectromagnetics.

[50]  D. Weiss,et al.  Effects of 50 Hz EMF exposure on micronucleus formation and apoptosis in transformed and nontransformed human cell lines , 1998 .

[51]  J. Chiu,et al.  Comparative proteomic analysis of differentiation of mouse F9 embryonic carcinoma cells induced by retinoic acid , 2012, Journal of cellular biochemistry.

[52]  R. Goodman,et al.  ERK1/2 phosphorylation, induced by electromagnetic fields, diminishes during neoplastic transformation , 2000, Journal of cellular biochemistry.

[53]  N. Shepherd,et al.  The assessment of proliferating cell nuclear antigen (PCNA) immunostaining in primary gastrointestinal lymphomas and its relationship to histological grade, S + G2 + M phase fraction (flow cytometric analysis) and prognosis , 1991, Histopathology.

[54]  A. D. de Lera,et al.  Rapid, nongenomic actions of retinoic acid on phosphatidylinositol-3-kinase signaling pathway mediated by the retinoic acid receptor. , 2007, Molecular endocrinology.

[55]  B. Giese Electron transfer through DNA and peptides. , 2006, Bioorganic & medicinal chemistry.

[56]  D. House,et al.  The influence of 1.2 microT, 60 Hz magnetic fields on melatonin- and tamoxifen-induced inhibition of MCF-7 cell growth. , 2001, Bioelectromagnetics.

[57]  Deleana Pozzi,et al.  Differentiation of human adult cardiac stem cells exposed to extremely low-frequency electromagnetic fields. , 2009, Cardiovascular research.

[58]  R. Goodman,et al.  Myc‐mediated transactivation of HSP70 expression following exposure to magnetic fields , 1998, Journal of cellular biochemistry.

[59]  S. Kanao,et al.  No effect of extremely low‐frequency magnetic field observed on cell growth or initial response of cell proliferation in human cancer cell lines , 2002, Bioelectromagnetics.

[60]  Niels Kuster,et al.  The FASEB Journal express article 10.1096/fj.04-3549fje. Published online August 22, 2005. , 2022 .

[61]  D. House,et al.  Evidence for direct effect of magnetic fields on neurite outgrowth , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[62]  M. Egger,et al.  Residence near power lines and mortality from neurodegenerative diseases: longitudinal study of the Swiss population. , 2008, American journal of epidemiology.

[63]  E. Sobel,et al.  Long-term exposure to magnetic fields and the risks of Alzheimer's disease and breast cancer: Further biological research. , 2009, Pathophysiology : the official journal of the International Society for Pathophysiology.

[64]  J. Arellanes-Robledo,et al.  Anti-proliferative effect of extremely low frequency electromagnetic field on preneoplastic lesions formation in the rat liver , 2010, BMC Cancer.

[65]  D. Conti,et al.  Absence of genotoxicity in human blood cells exposed to 50 Hz magnetic fields as assessed by comet assay, chromosome aberration, micronucleus, and sister chromatid exchange analyses , 2004, Bioelectromagnetics.

[66]  T. Suthiphongchai,et al.  Involvement of PI3K and ERK1/2 pathways in hepatocyte growth factor-induced cholangiocarcinoma cell invasion. , 2010, World Journal of Gastroenterology.

[67]  Rony Seger,et al.  The MEK/ERK cascade: from signaling specificity to diverse functions. , 2007, Biochimica et biophysica acta.

[68]  A. Zewail,et al.  Femtosecond direct observation of charge transfer between bases in DNA. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[69]  A A Afifi,et al.  Occupational Electric and Magnetic Field Exposure and Brain Cancer: A Meta‐Analysis , 1995, Journal of occupational and environmental medicine.

[70]  L. Thal,et al.  Astroglial Activation of Extracellular-Regulated Kinase in Early Stages of Alzheimer Disease , 2006, Journal of neuropathology and experimental neurology.

[71]  M. Karsy,et al.  All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. , 2010, Anticancer research.

[72]  Pietro L. Indovina,et al.  Cellular effects of extremely low frequency (ELF) electromagnetic fields , 2009, International journal of radiation biology.

[73]  Wolfgang Löscher,et al.  Exposure of Fischer 344 rats to a weak power frequency magnetic field facilitates mammary tumorigenesis in the DMBA model of breast cancer. , 2007, Carcinogenesis.

[74]  G. Eichholz Non-ionizing Radiation, Part 1: Static and Extremely Low-frequency (elf) Electric and Magnetic Fields, , 2002 .

[75]  Arthur,et al.  Inhibition of the LSD 1 ( KDM 1 A ) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia , 2013 .

[76]  K. H. Mild,et al.  Effects of 50-Hz magnetic field exposure on superoxide radical anion formation and HSP70 induction in human K562 cells , 2010, Radiation and environmental biophysics.

[77]  K. Jokela,et al.  ICNIRP Guidelines GUIDELINES FOR LIMITING EXPOSURE TO TIME-VARYING , 1998 .

[78]  Y. Takasaki,et al.  Prognostic value of proliferating cell nuclear antigen (PCNA) immunostaining in neuroblastoma. , 1995, Medical and pediatric oncology.

[79]  Jun Kawamata,et al.  Stimulating nicotinic receptors trigger multiple pathways attenuating cytotoxicity in models of Alzheimer's and Parkinson's diseases. , 2011, Journal of Alzheimer's disease : JAD.

[80]  N. Kuster,et al.  DNA fragmentation in human fibroblasts under extremely low frequency electromagnetic field exposure. , 2010, Mutation research.

[81]  G. Ziegelberger,et al.  International commission on non-ionizing radiation protection. , 2006, Progress in biophysics and molecular biology.

[82]  M. Trillo,et al.  A 50 Hz magnetic field blocks melatonin-induced enhancement of junctional transfer in normal C3H/10T1/2 cells. , 1995, Carcinogenesis.

[83]  Michael Repacholi Concern that "EMF" magnetic fields from power lines cause cancer. , 2012, The Science of the total environment.

[84]  V. Caracciolo,et al.  Fifty hertz extremely low‐frequency magnetic field exposure elicits redox and trophic response in rat‐cortical neurons , 2009, Journal of cellular physiology.

[85]  M. Mena,et al.  Functional implications of the noradrenergic‐cholinergic switch induced by retinoic acid in NB69 neuroblastoma cells , 2000, Journal of neuroscience research.

[86]  Maria Feychting,et al.  Electromagnetic Fields and Female Breast Cancer , 2006, Cancer Causes & Control.

[87]  Channakeshava,et al.  Influence of extremely low frequency magnetic fields on Ca2+ signaling and NMDA receptor functions in rat hippocampus , 2007, Neuroscience Letters.

[88]  R. Kavet,et al.  Future needs of occupational epidemiology of extremely low frequency electric and magnetic fields: review and recommendations , 2008, Occupational and Environmental Medicine.

[89]  T. He,et al.  All-trans retinoic acid inhibits tumor growth of human osteosarcoma by activating Smad signaling-induced osteogenic differentiation. , 2012, International journal of oncology.

[90]  Sumit Jain,et al.  Human cord blood-derived multipotent stem cells (CB-SCs) treated with all-trans-retinoic acid (ATRA) give rise to dopamine neurons. , 2012, Biochemical and biophysical research communications.

[91]  Tore Tynes,et al.  Residential and occupational exposures to 50-Hz magnetic fields and breast cancer in women: a population-based study. , 2004, American journal of epidemiology.

[92]  Myrtill Simkó,et al.  Extremely low frequency electromagnetic fields as effectors of cellular responses in vitro: Possible immune cell activation , 2004, Journal of cellular biochemistry.

[93]  S Di Luzio,et al.  Extremely low frequency electromagnetic field enhances human keratinocyte cell growth and decreases proinflammatory chemokine production , 2008, The British journal of dermatology.

[94]  C. Chu,et al.  Mitochondrially localized ERK 2 regulates mitophagy and autophagic cell stress : Implications for Parkinson ’ s disease , 2008 .

[95]  H. Rüdiger,et al.  Age-related effects on induction of DNA strand breaks by intermittent exposure to electromagnetic fields , 2003, Mechanisms of Ageing and Development.

[96]  H. Rüdiger,et al.  Intermittent extremely low frequency electromagnetic fields cause DNA damage in a dose-dependent way , 2003, International archives of occupational and environmental health.

[97]  Claudia Giliberti,et al.  Monitoring of people and workers exposure to the electric, magnetic and electromagnetic fields in an Italian national cancer Institute , 2008, Journal of experimental & clinical cancer research : CR.