title: Gold nanoparticles induce nuclear damage in breast cancer cells, which is further amplified by hyperthermia.
abstract: Gold nanoparticles have emerged as promising tools for cancer research and therapy, where they can promote thermal killing. The molecular mechanisms underlying these events are not fully understood. The geometry and size of gold nanoparticles can determine the severity of cellular damage. Therefore, small and big gold nanospheres as well as gold nanoflowers were evaluated side-by-side. To obtain quantitative data at the subcellular and molecular level, we assessed how gold nanoparticles, either alone or in combination with mild hyperthermia, altered the physiology of cultured human breast cancer cells. Our analyses focused on the nucleus, because this organelle is essential for cell survival. We showed that all the examined gold nanoparticles associated with nuclei. However, their biological effects were quantitatively different. Thus, depending on the shape and size, gold nanoparticles changed multiple nuclear parameters. They redistributed stress-sensitive regulators of nuclear biology, altered the nuclear morphology, reorganized nuclear laminae and envelopes, and inhibited nucleolar functions. In particular, gold nanoparticles reduced the de novo biosynthesis of RNA in nucleoli, the subnuclear compartments that produce ribosomes. While small gold nanospheres and nanoflowers, but not big gold nanospheres, damaged the nucleus at normal growth temperature, several of these defects were further exacerbated by mild hyperthermia. Taken together, the toxicity of gold nanoparticles correlated with changes in nuclear organization and function. These results emphasize that the cell nucleus is a prominent target for gold nanoparticles of different morphologies. Moreover, we demonstrated that RNA synthesis in nucleoli provides quantitative information on nuclear damage and cancer cell survival.
authors.affiliation: Department of Physiology, McGill University, Montreal, H3G 1Y6, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kodiha
authors.forename: Eliza
authors.initials: E
authors.lastname: Hutter
authors.forename: Sebastien
authors.initials: S
authors.lastname: Boridy
authors.forename: Michal
authors.initials: M
authors.lastname: Juhas
authors.forename: Dusica
authors.initials: D
authors.lastname: Maysinger
authors.forename: Ursula
authors.initials: U
authors.lastname: Stochaj
mesh_terms: D001943:Breast Neoplasms / Q000628:therapy*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D061986:MCF-7 Cells; D053768:Metal Nanoparticles / Q000737:chemistry*; D018613:Microscopy, Confocal; D036103:Nanotechnology / Q000379:methods*; D012270:Ribosomes / Q000378:metabolism; D013778:Tetrazolium Salts / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry
chemical_list: D005456:Fluorescent Dyes; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue
references.citation: Cancer Chemother Pharmacol. 2010 Aug;66(3):535-45
references.pmid: 20012863
references.citation: Apoptosis. 2003 Jan;8(1):39-44
references.pmid: 12510150
references.citation: Am J Physiol Cell Physiol. 2005 Oct;289(4):C1034-41
references.pmid: 15930140
references.citation: Cancer Invest. 2005;23(7):599-608
references.pmid: 16305988
references.citation: Dalton Trans. 2011 Oct 14;40(38):9789-94
references.pmid: 21879078
references.citation: Nucleus. 2012 Nov-Dec;3(6):540-51
references.pmid: 22929227
references.citation: Nanotechnology. 2011 Sep 23;22(38):385601
references.pmid: 21878721
references.citation: Acc Chem Res. 2008 Dec;41(12):1578-86
references.pmid: 18447366
references.citation: Int J Cancer. 2003 Sep 10;106(4):486-95
references.pmid: 12845642
references.citation: J Med Chem. 2010 Jun 24;53(12):4585-602
references.pmid: 20334364
references.citation: J Biol Chem. 2010 Jul 9;285(28):21858-67
references.pmid: 20457599
references.citation: Am J Physiol Cell Physiol. 2011 Dec;301(6):C1307-15
references.pmid: 21918180
references.citation: Anal Chim Acta. 2008 Sep 19;626(1):37-43
references.pmid: 18761119
references.citation: FEBS Lett. 2009 Nov 3;583(21):3405-11
references.pmid: 19800331
references.citation: Anal Chem. 2011 Apr 1;83(7):2461-8
references.pmid: 21355549
references.citation: Biol Chem. 2010 May;391(5):481-9
references.pmid: 20302520
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):574-85
references.pmid: 17519961
references.citation: Mol Cell. 2010 Oct 22;40(2):216-27
references.pmid: 20965417
references.citation: Microsc Res Tech. 2011 Jul;74(7):592-604
references.pmid: 20830812
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8760-5
references.pmid: 20410458
references.citation: Methods Mol Biol. 2010;624:83-99
references.pmid: 20217590
references.citation: Cell Mol Life Sci. 2008 Jun;65(11):1756-67
references.pmid: 18425415
references.citation: EMBO J. 1984 Dec 20;3(13):3095-100
references.pmid: 6441707
references.citation: Biochem Biophys Res Commun. 2009 Jan 2;378(1):6-9
references.pmid: 19010308
references.citation: J Histochem Cytochem. 2010 Jul;58(7):635-51
references.pmid: 20385787
references.citation: PLoS One. 2013 Nov 06;8(11):e80237
references.pmid: 24223222
references.citation: Acta Histochem. 2008;110(3):210-6
references.pmid: 18160100
references.citation: Nanotechnology. 2010 Mar 12;21(10):105105
references.pmid: 20154383
references.citation: Small. 2010 Mar 22;6(6):745-52
references.pmid: 20183810
references.citation: Histopathology. 2009 May;54(6):753-62
references.pmid: 19178588
references.citation: Sci Signal. 2008 Sep 16;1(37):pl2
references.pmid: 18799422
references.citation: Langmuir. 2008 Oct 21;24(20):11860-5
references.pmid: 18817428
references.citation: Exp Cell Res. 2010 Oct 15;316(17):2969-81
references.pmid: 20688056
references.citation: Cell. 2007 Aug 24;130(4):638-50
references.pmid: 17719542
references.citation: BMC Cell Biol. 2011 Jun 03;12:25
references.pmid: 21639891
references.citation: Small. 2011 Jan 17;7(2):169-83
references.pmid: 21213377
references.citation: J Am Chem Soc. 2008 Aug 13;130(32):10643-7
references.pmid: 18642918
references.citation: J Clin Pathol. 2004 Jul;57(7):755-61
references.pmid: 15220371
references.citation: ACS Nano. 2011 Jun 28;5(6):4319-28
references.pmid: 21609027
references.citation: Nano Lett. 2007 Jun;7(6):1542-50
references.pmid: 17465586
references.citation: ACS Nano. 2010 May 25;4(5):2595-606
references.pmid: 20329742
references.citation: J Biol Chem. 2006 Jan 13;281(2):1296-304
references.pmid: 16286466
references.citation: Biomaterials. 2010 Oct;31(30):7606-19
references.pmid: 20656344
references.citation: Nano Lett. 2011 Jul 13;11(7):2938-43
references.pmid: 21667930
references.citation: J Chromatogr A. 2011 Jul 8;1218(27):4234-9
references.pmid: 21288528
references.citation: PLoS One. 2009 Sep 25;4(9):e7147
references.pmid: 19779612
references.citation: Nat Rev Mol Cell Biol. 2013 Jan;14(1):13-24
references.pmid: 23212477
references.citation: Nanotechnology. 2008 Aug 6;19(31):315102
references.pmid: 21828779
references.citation: J Exp Clin Cancer Res. 2007 Mar;26(1):91-9
references.pmid: 17550137
references.citation: Nat Mater. 2011 Jun 19;10(7):545-52
references.pmid: 21685903
references.citation: Annu Rev Biomed Eng. 2012;14:1-16
references.pmid: 22524388
references.citation: Nano Lett. 2012 Aug 8;12(8):4164-71
references.pmid: 22817451