RESISTANCE OF AIDS-ASSOCIATED KAPOSIS-SARCOMA CELLS TO FAS-MEDIATED APOPTOSIS

Escape of tumor cells from apoptotic-mediated stimuli results in tumor cell survival and resistance to cytotoxic mechanisms. Iiaposi's sarco ma (KS) is the most common malignancy associated with AIDS, although i ts pathogenesis is not known, It is clinically important to determine whether AIDS-KS cells are resistant to apoptosis via the Fas system, T hree isolates of AIDS-KS cells were studied, Although all KS cells exp ress Fas on the cell surface, these cells were resistant to cytotoxic anti-Fas antibody (IgM, CH-11). Treatment of AIDS-KS cells with actino mycin D sensitized the tumor cells to anti-Fas cytotoxicity and apopto sis. Apoptosis was assessed by morphological changes and DNA fragmenta tion analysis, Three possible mechanisms related to AIDS-KS cells, res istance to anti-Fas cytotoxicity were examined, First, synthesis and s ecretion of soluble Fas by the tumor cells can neutralize antibody-ind uced cytotoxicity. However, none of the three types of KS cells expres sed soluble Fas mRNA as determined by reverse transcription (RT)-PCR. Second, the expression of the proto-oncogene bcl-2 can protect cells f rom apoptotic signals, Analysis of bcl-2 mRNA by RT-PCR revealed that all three AIDS-KS cells express very low levels of bcl-2 mRNA, Third, the Fas-associated phosphatase-l (FAP-1) is an antiapoptotic molecule reported to interact with Fas and can block transduction of the apopto tic signal, RT-PCR analysis revealed that all three types of AIDS-KS c ells express high levels of FAP-I mRNA, and treatment of KS cells with actinomycin D reduced the levels of FAP-I mRNA significantly, These f indings demonstrate that AIDS-KS cells are resistant to Fas-mediated a poptosis and suggest that FAP-I may be involved in the acquisition of resistance of AIDS-KS to anti-Fas antibody-mediated apoptosis.