PCB-153 exposure coordinates cell cycle progression and cellular metabolism in human mammary epithelial cells.
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.
Venkatesha
Venkatasubbaiah A
VA
Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, 500 Newton Road, Iowa City, IA 52242-1181, USA.
Kalen
Amanda L
AL
Sarsour
Ehab H
EH
Goswami
Prabhat C
PC
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
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
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