Implications for oxidative and nitrative stress in the pathogenesis of AIDS-related Kaposi's sarcoma

AIDS-related Kaposi's sarcoma (AIDS-KS), which is the most prevalent AIDS related cancer, arises in a unique environment characterized by profound immunosuppression in conjunction with sustained immunostimulation. Persistent inflammation and the accompanying increased production of reactive species can promote carcinogenesis by numerous routes including sustained cell proliferation, initiation of nuclear and mitochondrial DNA mutations and induction of a proangiogenic environment. Furthermore, during conditions of continuous inflammation, protein nitration can result in irreversible inactivation of enzymes including the cytoprotective and reactive species degrading enzyme, mitochondrial superoxide dismutase (MnSOD). Because MnSOD serves as a putative tumor suppressor gene in addition to its reactive species inactivating capacities, the loss of MnSOD's cytoprotective functions could markedly facilitate malignant transformation. The purpose of this study was to investigate biochemical and molecular pathways by which reactive species facilitate AIDS-KS pathogenesis. Immunohistochemical studies of AIDS-KS tumors showed intense AIDS-KS lesional cell staining for MnSOD, inducible nitric oxide synthase (NOS 2) and the presence of a cellular 'fingerprint' of nitrative stress, 3-nitrotyrosine. Collectively, these results that imply reactive species stress occurs in situ. Similarly, cultured AIDS-KS cells derived from the AIDS-KS tumors contained both MnSOD protein and the 'high output' isoform, NOS 2. Co-localization studies established that the mitochondria are a primary site for 3-nitrotyrosine localization and immunoprecipitation/immunoblotting experiments confirmed that MnSOD tyrosine nitration occurs in AIDS-KS cells. Functional SOD assays showed that AIDS-KS cells possess significantly lower MnSOD activity relative to matched control cells; findings which correspond with ongoing MnSOD tyrosine nitration and subsequent inactivation within AIDS-KS cells. These results, which show in situ evidence of reactive species stress within AIDS-KS tumors and functional deficits attributable to nitrative stress in tumor-derived AIDS-KS lesional cells, imply that reactive species are intimately associated with AIDS-KS pathogenesis and provide insights for development of novel strategies for AIDS-KS clinical treatments.