title: Gossypol induces apoptosis in ovarian cancer cells through oxidative stress.
abstract: In the present work, metabolomic and redox proteomic analyses were carried out on an untreated- and gossypol-treated ovarian cancer cell line, SKOV3. Gossypol treatment resulted in cell death through oxidative stress. Metabolite analysis showed that gossypol induces a decrease of the cellular levels of GSH, aspartic acid, and FAD. Using a combination of double labeling and LC-MS-MS, we identified changes in thiol-redox states of 545 cysteine-containing peptides from 356 proteins. The frequently occurring amino acid residue immediately before or after the cysteine in these peptides is the non-polar and neutral leucine, valine, or alanine. These redox sensitive proteins participate in a variety of cellular processes. We have characterized the redox-sensitive cysteine residues in PKM2, HSP60, malate dehydrogenase and other proteins that play important roles in metabolism homeostasis and stress responses. The three cysteine residues of HSP60 exhibit different responses to gossypol treatment: an increase of thiol/disulfide ratio for the Cys447 residue due to a decrease of the cellular GSH level, and a decrease of thiol/disulfide ratios for Cys442 and Cys237 residues due to oxidation and sulfation. This study suggests that thiol/disulfide ratios are dependent on the level of cellular GSH. Our data provide a valuable resource for deciphering the redox regulation of proteins and for understanding gossypol-induced apoptosis in ovarian cancer cells.
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.forename: Lixu
authors.initials: L
authors.lastname: Jin
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Haiyun
authors.initials: H
authors.lastname: Deng
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chen
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Lian
authors.forename: Renshan
authors.initials: R
authors.lastname: Ge
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
mesh_terms: D017209:Apoptosis; D001224:Aspartic Acid / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D018834:Chaperonin 60 / Q000378:metabolism; D003272:Contraceptive Agents, Male / Q000494:pharmacology; D004220:Disulfides / Q000378:metabolism; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D055432:Metabolomics; D024101:Mitochondrial Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020543:Proteome; D040901:Proteomics; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D001224:Aspartic Acid; D002352:Carrier Proteins; D018834:Chaperonin 60; D003272:Contraceptive Agents, Male; D004220:Disulfides; D005182:Flavin-Adenine Dinucleotide; D005978:Glutathione; D006072:Gossypol; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020543:Proteome; D013438:Sulfhydryl Compounds; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C060293:HSPD1 protein, human