title: Role of lipid peroxidation in cellular responses to D,L-sulforaphane, a promising cancer chemopreventive agent.
abstract: D,L-sulforaphane (SFN), a synthetic analogue of the broccoli-derived l-isomer, is a highly promising cancer chemopreventive agent substantiated by inhibition of chemically induced cancer in rodents and prevention of cancer development and distant site metastasis in transgenic mouse models of cancer. SFN is also known to inhibit growth of human cancer cells in association with cell cycle arrest and reactive oxygen species-dependent apoptosis, but the mechanism of these cellular responses to SFN exposure is not fully understood. Because 4-hydroxynonenal (4-HNE), a product of lipid peroxidation (LPO), the formation of which is regulated by hGSTA1-1, assumes a pivotal role in oxidative stress-induced signal transduction, we investigated its contribution in growth arrest and apoptosis induction by SFN using HL60 and K562 human leukemic cell lines as a model. The SFN-induced formation of 4-HNE was suppressed in hGSTA1-1-overexpressing cells, which also acquired resistance to SFN-induced cytotoxicity, cell cycle arrest, and apoptosis. While resistance to SFN-induced cell cycle arrest by ectopic expression of hGSTA1-1 was associated with changes in levels of G2/M regulatory proteins, resistance to apoptosis correlated with an increased Bcl-xL/Bax ratio, inhibition of nuclear translocation of AIF, and attenuated cytochrome c release in cytosol. The hGSTA1-1-overexpressing cells exhibited enhanced cytoplasmic export of Daxx, nuclear accumulation of transcription factors Nrf2 and HSF1, and upregulation of their respective client proteins, gamma-GCS and HSP70. These findings not only reveal a central role of 4-HNE in cellular responses to SFN but also reaffirm that 4-HNE contributes to oxidative stress-mediated signaling.
authors.affiliation: Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. rsharma@hsc.unt.edu
authors.forename: Rajendra
authors.initials: R
authors.lastname: Sharma
authors.forename: Abha
authors.initials: A
authors.lastname: Sharma
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaudhary
authors.forename: Virginia
authors.initials: V
authors.lastname: Pearce
authors.forename: Rit
authors.initials: R
authors.lastname: Vatsyayan
authors.forename: Shivendra V
authors.initials: SV
authors.lastname: Singh
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.forename: Yogesh C
authors.initials: YC
authors.lastname: Awasthi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D018922:HL-60 Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D017879:Isothiocyanates; D020014:K562 Cells; D015227:Lipid Peroxidation; D018832:Molecular Chaperones; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: C494829:AIFM1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016588:Anticarcinogenic Agents; D051033:Apoptosis Inducing Factor; C494811:BCL2L1 protein, human; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D017879:Isothiocyanates; D018832:Molecular Chaperones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009687:Nuclear Proteins; D013454:Sulfoxides; D013861:Thiocyanates; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C484555:GSTA1 protein, human; D005982:Glutathione Transferase; C016766:sulforaphane