ANTI-CELL DEATH ACTIVITY PROMOTES PULMONARY METASTASIS OF MELANOMA-CELLS

Bcl-2 inhibits apoptosis from a variety of stimuli, and a Bcl-2-bindin g protein BAG-1 also functions in protection from apoptosis in concert with Bcl-2, Here, we provide evidence that prolonged cell survival in troduced by overexpression of Bcl-2 or BAG-1 proteins strongly promote s experimental pulmonary metastasis of melanoma B16-BL6 cells, In muri ne melanoma cell line B16-BL6, gene transfer-mediated expression of th e Bcl-2 or BAG-1 led to prolonged cell survival against serum-starved apoptosis in vitro, The Bcl-2-expressing B16 cells, B16-Bcl-2 and the BAG-1-expressing B16 cells, B16-BAG-1 strongly enhanced pulmonary meta stasis in allogenic BALB/c nude mice and whole lung weights were incre ased by 2.4-fold and 1.4-fold, respectively, compared with control tra nsfectants, suggesting that Bcl-2 is a stronger positive modulator of metastasis, When the viable B16-Bcl-2 and control transfectants were i njected subcutaneously into BALB/c nude mice, the colony numbers of pu lmonary metastasis of the B16-Bcl-2 transfectant increased by 5.6-fold compared with the control transfectants, These enhanced metastatic po tentials in the B16-Bcl-2 and the B16-BAG-1 transfectants were well co rrelated with anti-cell death activity against serum-starvation and en hanced cell viability on limiting dilution, Analysis of the transfecta nts however revealed that their growth rates, invasive ability and cel l motility were not significantly altered by overexpression of either Bcl-2 or BAG-1 proteins, Taken together, these studies demonstrate tha t prolonged cell survival is a crucial factor to promote metastasis of melanoma, thereby contributing to tumor progression.