INDUCTION OF APOPTOSIS IN KAPOSIS-SARCOMA SPINDLE-CELL CULTURES BY THE SUBUNITS OF HUMAN CHORIONIC-GONADOTROPIN

Objectives: Elucidation of the mechanisms of the previously shown grow th-inhibitory action of human chorionic gonadotropin (hCG) on Kaposi's sarcoma (KS) cells and the role of the luteinizing hormone/hCG recept or (hCGR). Design and methods: Analysis of KS tissues and cultured spi ndle-type KS cells for the presence of the hCGR using (125)1-hCG bindi ng and reverse transcriptase-polymerase chain reaction; analysis of se veral hCG preparations (urinary, recombinant, isolated alpha and beta subunits); analysis of apoptosis mechanisms by several assays includin g using z-Val-Ala-Asp-fluoromethylketone (zVAD-FMK), a known apoptosis -inhibitory drug. Results: First, we found that some urinary preparati ons of hCC (e.g., CC-10, Steris Profasi) were indeed KS-killing but ot hers (such as Pregnyl, Choragon, Serono Profasi) were not. Secondly, r ecombinant subunits (alpha as well as beta) of hCG were KS cell-killin g but recombinant intact hCC was not. Thirdly, the hCGR message and pr otein were undetectable in KS. Fourthly, CG10-induced cell death occur red by apoptosis and KS cells could be rescued by preincubation with z VAD-FMK. Finally, we also found that normal peripheral blood lymphocyt es (PBL) were killed by CC-10. Conclusion: It is proposed that the act ion of subunits or subunit fragments of hCC, mediated by a putative or phan receptor (as opposed to the hCCR) and executed by interleukin-1-c onverting enzyme (ICE)-like protease(s), constitutes a novel apoptosis mechanism effective towards KS cells, but PBLs and possibly other cel ls as well. These results provide a basis for testing in vitro the the rapeutic efficacy of hCG preparations which, in turn, should improve c urrent clinical trials with 'hCC' in patients who have KS.