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Archives of Toxicology

, Volume 93, Issue 5, pp 1265–1279 | Cite as

Cell–cell contacts protect against t-BuOOH-induced cellular damage and ferroptosis in vitro

  • Christine Wenz
  • Dagmar Faust
  • Berenike Linz
  • Christian Turmann
  • Teodora Nikolova
  • Cornelia DietrichEmail author
Molecular Toxicology
  • 483 Downloads

Abstract

Ferroptosis is a recently discovered pathway of regulated necrosis dependent on iron and lipid peroxidation. It has gained broad attention since it is a promising approach to overcome resistance to apoptosis in cancer chemotherapy. We have recently identified tertiary-butyl hydroperoxide (t-BuOOH) as a novel inducer of ferroptosis. t-BuOOH is a widely used compound to induce oxidative stress in vitro. t-BuOOH induces lipid peroxidation and consequently ferroptosis in murine and human cell lines. t-BuOOH additionally results in a loss of mitochondrial membrane potential, formation of DNA double-strand breaks, and replication block. Here, we specifically address the question whether cell–cell contacts regulate t-BuOOH-induced ferroptosis and cellular damage. To this end, murine NIH3T3 or human HaCaT cells were seeded to confluence, but below their saturation density to allow the establishment of cell–cell contacts without inducing quiescence. Cells were then treated with t-BuOOH (50 or 200 µM, respectively). We revealed that cell–cell contacts reduce basal and t-BuOOH-triggered lipid peroxidation and consequently block ferroptosis. Similar results were obtained with the specific ferroptosis inducer erastin. Cell–cell contacts further protect against t-BuOOH-induced loss of mitochondrial membrane potential, and formation of DNA double-strand breaks. Interestingly, cell–cell contacts failed to prevent t-BuOOH-mediated replication block or formation of the oxidative base lesion 8-oxo-dG. Since evidence of protection against cell death was both (i) observed after treatment with hydrogen peroxide, methyl methanesulfonate or UV-C, and (ii) seen in several cell lines, we conclude that protection by cell–cell contacts is a widespread phenomenon. The impact of cell–cell contacts on toxicity might have important implications in cancer chemotherapy.

Keywords

Cell-cell contacts Oxidative stress t-BuOOH Ferroptosis Resistance 

Notes

Acknowledgements

We thank Bernd Epe for fruitful discussions. We are indebted to Anna Frumkina for expert technical assistance. The technical support by Julia Altmaier, FACS and Array Core Facility, is gratefully acknowledged. The work was supported by the Stipendienstiftung Rheinland-Pfalz, Hoffmann-Klose-Stiftung, Johannes Gutenberg-University, and University Medical Center of the Johannes Gutenberg-University and is part of the Ph.D. thesis of CW, and the MD theses of BL, and CT.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

204_2019_2413_MOESM1_ESM.pdf (14.1 mb)
Supplementary material 1 (PDF 14395 KB)

References

  1. Aceto N, Bardia A, Miyamoto DT et al (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158(5):1110–1122.  https://doi.org/10.1016/j.cell.2014.07.013 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Angeli JPF, Shah R, Pratt DA, Conrad M (2017) Ferroptosis inhibition: mechanisms and opportunities. Trends Pharmacol Sci 38(5):489–498.  https://doi.org/10.1016/j.tips.2017.02.005 CrossRefPubMedGoogle Scholar
  3. Avery SV (2011) Molecular targets of oxidative stress. Biochem J 434(2):201–210.  https://doi.org/10.1042/BJ20101695 CrossRefPubMedGoogle Scholar
  4. Ayala A, Munoz MF, Arguelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:360438.  https://doi.org/10.1155/2014/360438 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bakondi E, Gonczi M, Szabo E et al (2003) Role of intracellular calcium mobilization and cell-density-dependent signaling in oxidative-stress-induced cytotoxicity in HaCaT keratinocytes. J Invest Dermatol 121(1):88–95.  https://doi.org/10.1046/j.1523-1747.2003.12329.x CrossRefPubMedGoogle Scholar
  6. Bar J, Cohen-Noyman E, Geiger B, Oren M (2004) Attenuation of the p53 response to DNA damage by high cell density. Oncogene 23(12):2128–2137.  https://doi.org/10.1038/sj.onc.1207325 CrossRefPubMedGoogle Scholar
  7. Bellomo G, Jewell SA, Thor H, Orrenius S (1982) Regulation of intracellular calcium compartmentation: studies with isolated hepatocytes and t-butyl hydroperoxide. Proc Natl Acad Sci USA 79(22):6842–6846CrossRefGoogle Scholar
  8. Bellomo G, Martino A, Richelmi P, Moore GA, Jewell SA, Orrenius S (1984) Pyridine-nucleotide oxidation, Ca2 + cycling and membrane damage during tert-butyl hydroperoxide metabolism by rat-liver mitochondria. Eur J Biochem 140(1):1–6CrossRefGoogle Scholar
  9. Borcherding N, Cole K, Kluz P et al (2018) Re-Evaluating E-Cadherin and beta-catenin: a pan-cancer proteomic approach with an emphasis on breast cancer. Am J Pathol 188(8):1910–1920.  https://doi.org/10.1016/j.ajpath.2018.05.003 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE (1988) Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 106(3):761–771CrossRefGoogle Scholar
  11. Brabletz T, Jung A, Reu S et al (2001) Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 98(18):10356–10361.  https://doi.org/10.1073/pnas.171610498 CrossRefPubMedGoogle Scholar
  12. Chae B, Yang KM, Kim TI, Kim WH (2009) Adherens junction-dependent PI3K/Akt activation induces resistance to genotoxin-induced cell death in differentiated intestinal epithelial cells. Biochem Biophys Res Commun 378(4):738–743.  https://doi.org/10.1016/j.bbrc.2008.11.120 CrossRefPubMedGoogle Scholar
  13. Chung YC, Wei WC, Hung CN et al (2016) Rab11 collaborates E-cadherin to promote collective cell migration and indicates a poor prognosis in colorectal carcinoma. Eur J Clin Investig 46(12):1002–1011.  https://doi.org/10.1111/eci.12683 CrossRefGoogle Scholar
  14. Conrad M, Angeli JP, Vandenabeele P, Stockwell BR (2016) Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 15(5):348–366.  https://doi.org/10.1038/nrd.2015.6 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Conrad M, Kagan VE, Bayir H et al (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32(9–10):602–619.  https://doi.org/10.1101/gad.314674.118 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dietrich C, Wallenfang K, Oesch F, Wieser R (1997) Differences in the mechanisms of growth control in contact-inhibited and serum-deprived human fibroblasts. Oncogene 15(22):2743–2747.  https://doi.org/10.1038/sj.onc.1201439 CrossRefPubMedGoogle Scholar
  17. Dietrich C, Scherwat J, Faust D, Oesch F (2002) Subcellular localization of beta-catenin is regulated by cell density. Biochem Biophys Res Commun 292(1):195–199CrossRefGoogle Scholar
  18. Dixon SJ (2017) Ferroptosis: bug or feature? Immunol Rev 277(1):150–157.  https://doi.org/10.1111/imr.12533 CrossRefPubMedGoogle Scholar
  19. Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072.  https://doi.org/10.1016/j.cell.2012.03.042 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR (2007) p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer cell 11(2):191–205.  https://doi.org/10.1016/j.ccr.2006.12.013 CrossRefPubMedGoogle Scholar
  21. Dorsey JF, Dowling ML, Kim M, Voong R, Solin LJ, Kao GD (2010) Modulation of the anti-cancer efficacy of microtubule-targeting agents by cellular growth conditions. Cancer Biol Ther 9(10):809–818CrossRefGoogle Scholar
  22. Eagle H, Levine EM (1967) Growth regulatory effects of cellular interaction. Nature 213(5081):1102–1106CrossRefGoogle Scholar
  23. Eckl PM, Bresgen N (2017) Genotoxicity of lipid oxidation compounds. Free Radic Biol Med 111:244–252.  https://doi.org/10.1016/j.freeradbiomed.2017.02.002 CrossRefPubMedGoogle Scholar
  24. Elisha Y, Kalchenko V, Kuznetsov Y, Geiger B (2018) Dual role of E-cadherin in the regulation of invasive collective migration of mammary carcinoma cells. Sci Rep 8(1):4986.  https://doi.org/10.1038/s41598-018-22940-3 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Erez N, Zamir E, Gour BJ, Blaschuk OW, Geiger B (2004) Induction of apoptosis in cultured endothelial cells by a cadherin antagonist peptide: involvement of fibroblast growth factor receptor-mediated signalling. Exp Cell Res 294(2):366–378.  https://doi.org/10.1016/j.yexcr.2003.11.033 CrossRefPubMedGoogle Scholar
  26. Faust D, Dolado I, Cuadrado A et al (2005) p38alpha MAPK is required for contact inhibition. Oncogene 24(53):7941–7945.  https://doi.org/10.1038/sj.onc.1208948 CrossRefPubMedGoogle Scholar
  27. Feng H, Stockwell BR (2018) Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol 16(5):e2006203.  https://doi.org/10.1371/journal.pbio.2006203 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10(7):445–457.  https://doi.org/10.1038/nrm2720 CrossRefPubMedGoogle Scholar
  29. Friedmann Angeli JP, Schneider M, Proneth B et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191.  https://doi.org/10.1038/ncb3064 CrossRefPubMedGoogle Scholar
  30. Fulda S (2014) Therapeutic exploitation of necroptosis for cancer therapy. Semin Cell Dev Biol 35:51–56.  https://doi.org/10.1016/j.semcdb.2014.07.002 CrossRefPubMedGoogle Scholar
  31. Gaballah M, Slisz M, Hutter-Lobo D (2012) Role of JNK-1 regulation in the protection of contact-inhibited fibroblasts from oxidative stress. Mol Cell Biochem 359(1–2):105–113.  https://doi.org/10.1007/s11010-011-1004-1 CrossRefPubMedGoogle Scholar
  32. Galaz S, Espada J, Stockert JC et al (2005) Loss of E-cadherin mediated cell-cell adhesion as an early trigger of apoptosis induced by photodynamic treatment. J Cell Physiol 205(1):86–96.  https://doi.org/10.1002/jcp.20374 CrossRefPubMedGoogle Scholar
  33. Galluzzi L, Vitale I, Abrams JM et al (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19(1):107–120.  https://doi.org/10.1038/cdd.2011.96 CrossRefGoogle Scholar
  34. Galluzzi L, Kepp O, Krautwald S, Kroemer G, Linkermann A (2014) Molecular mechanisms of regulated necrosis. Semin Cell Dev Biol 35:24–32.  https://doi.org/10.1016/j.semcdb.2014.02.006 CrossRefPubMedGoogle Scholar
  35. Galluzzi L, Bravo-San Pedro JM, Vitale I et al (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 22(1):58–73.  https://doi.org/10.1038/cdd.2014.137 CrossRefPubMedGoogle Scholar
  36. Galluzzi L, Vitale I, Aaronson SA et al (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ.  https://doi.org/10.1038/s41418-017-0012-4 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Garcia-Cohen EC, Marin J, Diez-Picazo LD, Baena AB, Salaices M, Rodriguez-Martinez MA (2000) Oxidative stress induced by tert-butyl hydroperoxide causes vasoconstriction in the aorta from hypertensive and aged rats: role of cyclooxygenase-2 isoform. J Pharmacol Exp Ther 293(1):75–81PubMedGoogle Scholar
  38. Godwin TD, Kelly ST, Brew TP et al (2018) E-cadherin-deficient cells have synthetic lethal vulnerabilities in plasma membrane organisation, dynamics and function. Gastric Cancer.  https://doi.org/10.1007/s10120-018-0859-1 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Gujral TS, Kirschner MW (2017) Hippo pathway mediates resistance to cytotoxic drugs. Proc Natl Acad Sci USA 114(18):E3729–E3738.  https://doi.org/10.1073/pnas.1703096114 CrossRefPubMedGoogle Scholar
  40. Gutierrez-Uzquiza A, Arechederra M, Bragado P, Aguirre-Ghiso JA, Porras A (2012) p38alpha mediates cell survival in response to oxidative stress via induction of antioxidant genes: effect on the p70S6K pathway. J Biol Chem 287(4):2632–2642.  https://doi.org/10.1074/jbc.M111.323709 CrossRefPubMedGoogle Scholar
  41. Han HJ, Kwon HY, Sohn EJ et al (2014) Suppression of E-cadherin mediates gallotannin induced apoptosis in Hep G2 hepatocelluar carcinoma cells. Int J Biol Sci 10(5):490–499.  https://doi.org/10.7150/ijbs.7495 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Heit I, Wieser RJ, Herget T et al (2001) Involvement of protein kinase Cdelta in contact-dependent inhibition of growth in human and murine fibroblasts. Oncogene 20(37):5143–5154.  https://doi.org/10.1038/sj.onc.1204657 CrossRefPubMedGoogle Scholar
  43. Hengst L, Reed SI (1996) Translational control of p27Kip1 accumulation during the cell cycle. Science 271(5257):1861–1864CrossRefGoogle Scholar
  44. Jewell SA, Bellomo G, Thor H, Orrenius S, Smith M (1982) Bleb formation in hepatocytes during drug metabolism is caused by disturbances in thiol and calcium ion homeostasis. Science 217(4566):1257–1259CrossRefGoogle Scholar
  45. Jiang Y, Zhang XY, Sun L et al (2012) Methyl methanesulfonate induces apoptosis in p53-deficient H1299 and Hep3B cells through a caspase 2- and mitochondria-associated pathway. Environ Toxicol Pharmacol 34(3):694–704.  https://doi.org/10.1016/j.etap.2012.09.019 CrossRefPubMedGoogle Scholar
  46. Koizumi T, Hikiji H, Shin WS et al (2003) Cell density and growth-dependent down-regulation of both intracellular calcium responses to agonist stimuli and expression of smooth-surfaced endoplasmic reticulum in MC3T3-E1 osteoblast-like cells. J Biol Chem 278(8):6433–6439.  https://doi.org/10.1074/jbc.M210243200 CrossRefPubMedGoogle Scholar
  47. Kreuzaler P, Watson CJ (2012) Killing a cancer: what are the alternatives? Nat Rev Cancer 12(6):411–424.  https://doi.org/10.1038/nrc3264 CrossRefPubMedGoogle Scholar
  48. Kuppers M, Ittrich C, Faust D, Dietrich C (2010) The transcriptional programme of contact-inhibition. J Cell Biochem 110(5):1234–1243.  https://doi.org/10.1002/jcb.22638 CrossRefPubMedGoogle Scholar
  49. Lackinger D, Eichhorn U, Kaina B (2001) Effect of ultraviolet light, methyl methanesulfonate and ionizing radiation on the genotoxic response and apoptosis of mouse fibroblasts lacking c-Fos, p53 or both. Mutagenesis 16(3):233–241CrossRefGoogle Scholar
  50. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685CrossRefGoogle Scholar
  51. Leist M, Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2(8):589–598.  https://doi.org/10.1038/35085008 CrossRefPubMedGoogle Scholar
  52. Lemasters JJ, Theruvath TP, Zhong Z, Nieminen AL (2009) Mitochondrial calcium and the permeability transition in cell death. Biochim Biophys Acta 1787(11):1395–1401.  https://doi.org/10.1016/j.bbabio.2009.06.009 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Lewis-Tuffin LJ, Rodriguez F, Giannini C et al (2010) Misregulated E-cadherin expression associated with an aggressive brain tumor phenotype. PLoS One 5(10):e13665.  https://doi.org/10.1371/journal.pone.0013665 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Li G, Satyamoorthy K, Herlyn M (2001) N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 61(9):3819–3825PubMedGoogle Scholar
  55. Lu L, Liu X, Wang C, Hu F, Wang J, Huang H (2015) Dissociation of E-cadherin/beta-catenin complex by MG132 and bortezomib enhances CDDP induced cell death in oral cancer SCC-25 cells. Toxicol In Vitro 29(8):1965–1976.  https://doi.org/10.1016/j.tiv.2015.07.008 CrossRefPubMedGoogle Scholar
  56. Magtanong L, Ko PJ, Dixon SJ (2016) Emerging roles for lipids in non-apoptotic cell death. Cell Death Differ 23(7):1099–1109.  https://doi.org/10.1038/cdd.2016.25 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Matt S, Hofmann TG (2016) The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell Mol Life Sci 73(15):2829–2850.  https://doi.org/10.1007/s00018-016-2130-4 CrossRefPubMedGoogle Scholar
  58. Naderi J, Hung M, Pandey S (2003) Oxidative stress-induced apoptosis in dividing fibroblasts involves activation of p38 MAP kinase and over-expression of Bax: resistance of quiescent cells to oxidative stress. Apoptosis 8(1):91–100CrossRefGoogle Scholar
  59. Ng WH, Wan GQ, Too HP (2007) Higher glioblastoma tumour burden reduces efficacy of chemotherapeutic agents: in vitro evidence. J Clin Neurosci 14(3):261–266.  https://doi.org/10.1016/j.jocn.2005.11.010 CrossRefPubMedGoogle Scholar
  60. Nicotera P, McConkey D, Svensson SA, Bellomo G, Orrenius S (1988) Correlation between cytosolic Ca2 + concentration and cytotoxicity in hepatocytes exposed to oxidative stress. Toxicology 52(1–2):55–63CrossRefGoogle Scholar
  61. Peluso JJ (1997) Putative mechanism through which N-cadherin-mediated cell contact maintains calcium homeostasis and thereby prevents ovarian cells from undergoing apoptosis. Biochem Pharmacol 54(8):847–853CrossRefGoogle Scholar
  62. Peluso JJ, Pappalardo A, Trolice MP (1996) N-cadherin-mediated cell contact inhibits granulosa cell apoptosis in a progesterone-independent manner. Endocrinology 137(4):1196–1203.  https://doi.org/10.1210/endo.137.4.8625889 CrossRefPubMedGoogle Scholar
  63. Peluso JJ, Pappalardo A, Fernandez G (2001) E-cadherin-mediated cell contact prevents apoptosis of spontaneously immortalized granulosa cells by regulating Akt kinase activity. Biol Reprod 64(4):1183–1190CrossRefGoogle Scholar
  64. Pereira L, Igea A, Canovas B, Dolado I, Nebreda AR (2013) Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK. EMBO Mol Med 5(11):1759–1774.  https://doi.org/10.1002/emmm.201302732 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Pines J, Hunter T (1992) Cyclins A and B1 in the human cell cycle. Ciba Found Symp 170:187–196 (discussion 196–204)PubMedGoogle Scholar
  66. Polyak K, Kato JY, Solomon MJ et al (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8(1):9–22CrossRefGoogle Scholar
  67. Prakash A, Doublie S, Wallace SS (2012) The Fpg/Nei family of DNA glycosylases: substrates, structures, and search for damage. Progr Mol Biol Transl Sci 110:71–91.  https://doi.org/10.1016/b978-0-12-387665-2.00004-3 CrossRefGoogle Scholar
  68. Rancourt RC, Hayes DD, Chess PR, Keng PC, O’Reilly MA (2002) Growth arrest in G1 protects against oxygen-induced DNA damage and cell death. J Cell Physiol 193(1):26–36.  https://doi.org/10.1002/jcp.10146 CrossRefPubMedGoogle Scholar
  69. Rodriguez FJ, Lewis-Tuffin LJ, Anastasiadis PZ (2012) E-cadherin’s dark side: possible role in tumor progression. Biochim Biophys Acta 1826(1):23–31.  https://doi.org/10.1016/j.bbcan.2012.03.002 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Sakaida I, Thomas AP, Farber JL (1991) Increases in cytosolic calcium ion concentration can be dissociated from the killing of cultured hepatocytes by tert-butyl hydroperoxide. J Biol Chem 266(2):717–722PubMedGoogle Scholar
  71. Sedelnikova OA, Redon CE, Dickey JS, Nakamura AJ, Georgakilas AG, Bonner WM (2010) Role of oxidatively induced DNA lesions in human pathogenesis. Mut Res 704(1–3):152–159.  https://doi.org/10.1016/j.mrrev.2009.12.005 CrossRefGoogle Scholar
  72. Shih W, Yamada S (2012) N-cadherin-mediated cell-cell adhesion promotes cell migration in a three-dimensional matrix. J Cell Sci 125(Pt 15):3661–3670.  https://doi.org/10.1242/jcs.103861 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Smith PK, Krohn RI, Hermanson GT et al (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150(1):76–85CrossRefGoogle Scholar
  74. Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H, ME LL (2013) Oxidative stress and cancer: an overview. Ageing Res Rev 12(1):376–390.  https://doi.org/10.1016/j.arr.2012.10.004 CrossRefPubMedGoogle Scholar
  75. Stockwell BR, Friedmann Angeli JP, Bayir H et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171(2):273–285.  https://doi.org/10.1016/j.cell.2017.09.021 CrossRefPubMedPubMedCentralGoogle Scholar
  76. Swat A, Dolado I, Rojas JM, Nebreda AR (2009) Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38alpha mitogen-activated protein kinase via Sprouty2 downregulation. Mol Cell Biol 29(12):3332–3343.  https://doi.org/10.1128/mcb.01955-08 CrossRefPubMedPubMedCentralGoogle Scholar
  77. Telford BJ, Chen A, Beetham H et al (2015) Synthetic lethal screens identify vulnerabilities in GPCR signaling and cytoskeletal organization in E-cadherin-deficient Cells. Mol Cancer Ther 14(5):1213–1223.  https://doi.org/10.1158/1535-7163.mct-14-1092 CrossRefPubMedGoogle Scholar
  78. Tonnus W, Linkermann A (2017) The in vivo evidence for regulated necrosis. Immunol Rev 277(1):128–149.  https://doi.org/10.1111/imr.12551 CrossRefPubMedGoogle Scholar
  79. Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15(2):135–147.  https://doi.org/10.1038/nrm3737 CrossRefPubMedGoogle Scholar
  80. Vanlangenakker N, Vanden Berghe T, Vandenabeele P (2012) Many stimuli pull the necrotic trigger, an overview. Cell Death Differ 19(1):75–86.  https://doi.org/10.1038/cdd.2011.164 CrossRefPubMedGoogle Scholar
  81. Wang Y (2008) Bulky DNA lesions induced by reactive oxygen species. Chem Res Toxicol 21(2):276–281.  https://doi.org/10.1021/tx700411g CrossRefPubMedGoogle Scholar
  82. Wei CJ, Francis R, Xu X, Lo CW (2005) Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells. J Biol Chem 280(20):19925–19936.  https://doi.org/10.1074/jbc.M412921200 CrossRefPubMedGoogle Scholar
  83. Weiss C, Faust D, Schreck I et al (2008) TCDD deregulates contact inhibition in rat liver oval cells via Ah receptor, JunD and cyclin A. Oncogene 27(15):2198–2207.  https://doi.org/10.1038/sj.onc.1210859 CrossRefPubMedGoogle Scholar
  84. Wenz C, Faust D, Linz B et al (2018) t-BuOOH induces ferroptosis in human and murine cell lines. Arch Toxicol 92(2):759–775.  https://doi.org/10.1007/s00204-017-2066-y CrossRefPubMedGoogle Scholar
  85. Xiao M, Zhong H, Xia L, Tao Y, Yin H (2017) Pathophysiology of mitochondrial lipid oxidation: role of 4-hydroxynonenal (4-HNE) and other bioactive lipids in mitochondria. Free Radic Biol Med 111:316–327.  https://doi.org/10.1016/j.freeradbiomed.2017.04.363 CrossRefPubMedGoogle Scholar
  86. Xie Y, Hou W, Song X et al (2016) Ferroptosis: process and function. Cell Death Differ 23(3):369–379.  https://doi.org/10.1038/cdd.2015.158 CrossRefPubMedPubMedCentralGoogle Scholar
  87. Yagoda N, von Rechenberg M, Zaganjor E et al (2007) RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447(7146):864–868.  https://doi.org/10.1038/nature05859 CrossRefPubMedPubMedCentralGoogle Scholar
  88. Yamashita N, Tokunaga E, Iimori M et al (2018) Epithelial paradox: clinical significance of coexpression of E-cadherin and vimentin with regard to invasion and metastasis of breast cancer. Clin Breast Cancer 18(5):e1003–e1009.  https://doi.org/10.1016/j.clbc.2018.02.002 CrossRefPubMedGoogle Scholar
  89. Yamauchi T, Adachi S, Yasuda I et al (2011) Ultra-violet irradiation induces apoptosis via mitochondrial pathway in pancreatic cancer cells. Int J Oncol 39(6):1375–1380.  https://doi.org/10.3892/ijo.2011.1188 CrossRefPubMedGoogle Scholar
  90. Yang WS, Stockwell BR (2008) Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 15(3):234–245.  https://doi.org/10.1016/j.chembiol.2008.02.010 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26(3):165–176.  https://doi.org/10.1016/j.tcb.2015.10.014 CrossRefPubMedGoogle Scholar
  92. Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 113(34):E4966–E4975.  https://doi.org/10.1073/pnas.1603244113 CrossRefPubMedGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute of ToxicologyUniversity Medical Center of the Johannes Gutenberg-UniversityMainzGermany

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