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Cultured AIDS‐related kaposi's sarcoma (AIDS‐KS) cells demonstrate impaired bioenergetic adaptation to oxidant challenge: Implication for oxidant stress in AIDS‐KS pathogenesis
Author(s) -
Mallery S. R.,
Bailer R. T.,
Hohl C. M.,
NgBautista C. L.,
Ness G. M.,
Livingston B. E.,
Hout B. L.,
Stephens R. E.,
Brierley G. P.
Publication year - 1995
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.240590304
Subject(s) - tumor necrosis factor alpha , cytokine , oxidative stress , glutathione peroxidase , bioenergetics , reactive oxygen species , pathogenesis , glutathione , biology , cancer research , immunology , catalase , microbiology and biotechnology , biochemistry , enzyme , mitochondrion
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‐κB [NF‐κB] dependent routes) as well as the subsequent cytokine, tumor necrosis factor α (TNFα) 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 H 2 O 2 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. © 1995 Wiley‐Liss, Inc.