title: Cultured AIDS-related Kaposi's sarcoma (AIDS-KS) cells demonstrate impaired bioenergetic adaptation to oxidant challenge: implication for oxidant stress in AIDS-KS pathogenesis.
abstract: Despite its recognition as the most prevalent HIV associated cancer, speculation still abounds regarding the pathogenesis of AIDS-related Kaposi's sarcoma (AIDS-KS). However, it has been established that both cytokines, e.g. IL-6, and HIV-associated products, e.g., Tat, are integral in AIDS-KS cellular proliferation. Further, both experimental and clinical evidence is accumulating to link reactive oxygen intermediates (ROI) with both cytokine induction (primarily via nuclear factor-kappa B[NF-kappa B] dependent routes) as well as the subsequent cytokine, tumor necrosis factor alpha (TNF alpha) stimulation of HIV replication. Features of AIDS-KS patients, such as retention of phagocytes, presence of sustained immunostimulation, and a frequent history of KS lesions arising at traumatized sites, make oxidant stress a viable clinical factor in AIDS-KS development. Time course nucleotide profile analyses show that AIDS-KS cells have an inherent, statistically significant, biochemical deficit, even prior to oxidant stress, due to 1) a more glycolytic bioenergetic profile, resulting in lower levels of high energy phosphates (impairing capacity for glutathione [GSH] synthesis and DNA repair); 2) lower levels of NADPH (compromising the activities of GSSG reductase and peroxidase function of catalase); and 3) reduced levels of GSH (impeding both GSH peroxidase and GSH-S-transferases). Following exposure to physiologically relevant levels of H2O2, only the human microvascular endothelial cells (a putative AIDS-KS progenitor cell) responded with bioenergetic adaptations that reflected co-ordination of energy generating and cytoprotective pathways, e.g., retention of the cellular energy charge, increased NAD+, and an accentuation of the ATP, NADPH, and total adenine nucleotide differences relative to AIDS-KS cells. Also, some of the AIDS-KS strains retained intracellular GSSG subsequent to oxidant challenge, inviting the formation of deleterious protein mixed disulfides. While the results of our study address some AIDS-KS issues, they also raise an etiological question, i.e., Does the inability to tolerate oxidant stress arise in conjunction with AIDS-KS neoplastic development, or is it pre-existing in the population at risk? Regardless, use of antioxidant therapy (low risk/ potentially high benefit) in both the "at risk" population as well as in those individuals with active disease may prove a useful preventative and/or treatment modality.
authors.affiliation: Department of Dentistry, College of Dentistry, Ohio State University, Columbus 43210-1241, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Mallery
authors.forename: R T
authors.initials: RT
authors.lastname: Bailer
authors.forename: C M
authors.initials: CM
authors.lastname: Hohl
authors.forename: C L
authors.initials: CL
authors.lastname: Ng-Bautista
authors.forename: G M
authors.initials: GM
authors.lastname: Ness
authors.forename: B E
authors.initials: BE
authors.lastname: Livingston
authors.forename: B L
authors.initials: BL
authors.lastname: Hout
authors.forename: R E
authors.initials: RE
authors.lastname: Stephens
authors.forename: G P
authors.initials: GP
authors.lastname: Brierley
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000255:Adenosine Triphosphate / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D004734:Energy Metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D014357:Trypsin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D017382:Reactive Oxygen Species; D009243:NAD; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D014357:Trypsin; D005978:Glutathione