Induction of programmed cell death in Kaposi's sarcoma cells by preparations of human chorionic gonadotropin.

Abstract

Isolation of the first neoplastic acquired immunodeficiency syndrome-related Kaposi's sarcoma (KS) cell line (KS Y-1) has furthered understanding of the pathogenesis of KS. Studies with KS Y-1 cells have indicated that inhibition of KS cell proliferation occurs in early pregnancy in mice and after treatment with certain commercial preparations of human chorionic gonadotropin (hCG, a pregnancy hormone purified from urine). The activity of the commercial preparations has been attributed to an hCG-associated factor(s) (HAF). While several clinical benefits of HAF are clearly evident, the basis for its anti-KS properties remains unknown. We investigated the apoptosis-inducing effects of HAF and the expression of apoptosis-related proteins in KS cells. KS Y-1 and KS SLK cells were treated with clinical-grade crude preparations of hCG, recombinant hCG, or urine fractions exhibiting anti-KS activity and then examined for features of apoptosis. Levels of proteins associated with apoptosis were monitored by western blot analysis, and cell DNA content was assessed by flow cytometry. Tumors induced in mice by inoculation of KS Y-1 cells were treated with preparations of hCG, and the tumors were examined for cell morphology and also for DNA fragmentation by use of the terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine triphosphate nick-end-labeling (TUNEL) assay. The HAF present in some preparations of hCG and in urine fractions has the ability to induce apoptosis in KS cells in vitro and in vivo. HAF-triggered apoptosis was preceded by increased levels of the apoptosis-related proteins c-Myc and c-Rel and cell accumulation in Go/G1 phase of the cell cycle. KS Y-1 cells transfected with a c-Myc complementary DNA showed elevated rates of apoptosis. The anti-KS activity of HAF appears to induce apoptosis. Such activity suggests a role for HAF in pregnancy-related regulation of cell death.