Gossypol induces apoptosis in ovarian cancer cells through oxidative stress

Mol Biosyst. 2013 Jun;9(6):1489-97. doi: 10.1039/c3mb25461e. Epub 2013 Mar 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Aspartic Acid / metabolism
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Chaperonin 60 / metabolism
  • Contraceptive Agents, Male / pharmacology
  • Disulfides / metabolism
  • Female
  • Flavin-Adenine Dinucleotide / metabolism
  • Gene Expression Profiling
  • Glutathione / metabolism
  • Gossypol / pharmacology*
  • Humans
  • Membrane Proteins / metabolism
  • Metabolomics
  • Mitochondrial Proteins / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Oxidation-Reduction
  • Oxidative Stress*
  • Proteome
  • Proteomics
  • Sulfhydryl Compounds / metabolism
  • Thyroid Hormones / metabolism

Substances

  • Carrier Proteins
  • Chaperonin 60
  • Contraceptive Agents, Male
  • Disulfides
  • HSPD1 protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • Proteome
  • Sulfhydryl Compounds
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • Flavin-Adenine Dinucleotide
  • Aspartic Acid
  • Glutathione
  • Gossypol