title: PCB-153 exposure coordinates cell cycle progression and cellular metabolism in human mammary epithelial cells.
abstract: 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB-153) is a non-metabolizable environmental chemical contaminant commonly found in breast milk of PCB exposed individuals, suggesting that chronic exposure to PCB-153 could have adverse health effects. We have shown previously that PCB-153 increased reactive oxygen species levels in non-tumorigenic MCF-10A human mammary epithelial cells, which were associated with DNA damage, growth inhibition, and cytotoxicity. This study investigates the hypothesis that PCB-153 exposure coordinates cell cycle progression and cellular metabolism by inhibiting cyclin D1 accumulation. PCB-153 treated MCF-10A cells exhibited a dose and time dependent decrease in cyclin D1 protein levels. The decrease in cyclin D1 protein levels was associated with an inhibition in AKT and GSK-3beta phosphorylation, which correlated with an increase in cyclin D1-T286 phosphorylation. Fibroblasts carrying a mutant form of cyclin D1 (T286A) were resistant to PCB-153 induced degradation of cyclin D1. Pre-treatment of cells with a proteasome inhibitor (MG132) suppressed PCB-153 induced decrease in cyclin D1 protein levels. Interestingly, suppression in cyclin D1 accumulation was associated with an increase in cellular glucose consumption, and hexokinase II and pyruvate kinase protein levels. These results suggest that cyclin D1 coordinates cell cycle progression and cellular metabolism in PCB-153 treated non-tumorigenic human mammary epithelial cells.
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, 500 Newton Road, Iowa City, IA 52242-1181, USA.
authors.forename: Venkatasubbaiah A
authors.initials: VA
authors.lastname: Venkatesha
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kalen
authors.forename: Ehab H
authors.initials: EH
authors.lastname: Sarsour
authors.forename: Prabhat C
authors.initials: PC
authors.lastname: Goswami
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D013997:Time Factors
chemical_list: C530104:CCND1 protein, human; D004785:Environmental Pollutants; D007976:Leupeptins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019938:Cyclin D1; D011078:Polychlorinated Biphenyls; D006593:Hexokinase; D011770:Pyruvate Kinase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C014024:2,4,5,2',4',5'-hexachlorobiphenyl
references.citation: Toxicol Sci. 2005 Jan;83(1):64-77
references.pmid: 15509667
references.citation: Genes Dev. 1997 Apr 15;11(8):957-72
references.pmid: 9136925
references.citation: J Toxicol Environ Health A. 2006 Jan 8;69(1-2):139-58
references.pmid: 16291567
references.citation: Food Chem Toxicol. 2008 Jun;46(6):1925-32
references.pmid: 18321630
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11567-72
references.pmid: 16864783
references.citation: Mar Pollut Bull. 2005;51(8-12):794-800
references.pmid: 16291191
references.citation: Toxicol Sci. 2002 Aug;68(2):372-80
references.pmid: 12151633
references.citation: Cancer Res. 2003 May 1;63(9):2109-17
references.pmid: 12727827
references.citation: Toxicol Lett. 2006 Dec 15;167(3):183-90
references.pmid: 17049763
references.citation: Toxicol Sci. 2004 Sep;81(1):35-42
references.pmid: 15201435
references.citation: Toxicol Sci. 2006 Sep;93(1):34-40
references.pmid: 16782779
references.citation: Environ Int. 2009 Apr;35(3):580-7
references.pmid: 19058852
references.citation: Chem Res Toxicol. 1996 Apr-May;9(3):623-9
references.pmid: 8728508
references.citation: Int J Toxicol. 2006 Sep-Oct;25(5):341-7
references.pmid: 16940006
references.citation: Food Chem Toxicol. 2008 Jul;46(7):2561-7
references.pmid: 18508174
references.citation: Reproduction. 2005 Nov;130(5):731-42
references.pmid: 16264102
references.citation: Oncogene. 1995 Jul 20;11(2):211-9
references.pmid: 7624138
references.citation: Free Radic Biol Med. 2008 Oct 15;45(8):1094-102
references.pmid: 18691649
references.citation: J Biol Chem. 1999 Aug 6;274(32):22699-704
references.pmid: 10428852
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11211-6
references.pmid: 9736715
references.citation: Biochem Pharmacol. 1985 Oct 15;34(20):3735-9
references.pmid: 4052112
references.citation: Environ Toxicol Pharmacol. 2008 Mar;25(2):251-9
references.pmid: 18438459
references.citation: Environ Sci Technol. 2003 Jan 15;37(2):245-55
references.pmid: 12564894
references.citation: Mol Cell Biol. 2006 Jul;26(14):5449-69
references.pmid: 16809779
references.citation: J Immunol Methods. 1997 Jul 14;205(2):109-14
references.pmid: 9294591
references.citation: Toxicol Appl Pharmacol. 2008 Oct 15;232(2):302-8
references.pmid: 18644402
references.citation: Genes Dev. 2000 Dec 15;14(24):3102-14
references.pmid: 11124803
references.citation: Genes Dev. 1998 Nov 15;12(22):3499-511
references.pmid: 9832503