Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-gamma

The expression and functionality of the Fas receptor (CD95/APO-1) play an i mportant role for the maintenance of tissue homeostasis. Various types of t umor cells have been shown to escape immune recognition by constitutive res istance to CD95-mediated apoptosis, Furthermore, several apoptosis-related proteins have been reported to influence CD95 sensitivity. We tested an uns elected panel of 11 melanoma cell lines for sensitivity to CD95 and the cor responding expression of CD95, CD95L, bcl-2, bcl-x, bcl-xS, bar and FLIP pr oteins. Despite detection of CD95 cell-surface expression in 9 out of the 1 1 cell lines tested, only 3 melanoma cell lines were sensitive to anti-CD95 -MAb-induced cell death, Apoptosis-related proteins CD95L, bcl-2, bcl-x, bc l-xS and bar were found to be heterogenously expressed in different melanom a cell lines tested. The susceptibility of melanoma cells to anti-CD95-MAb- mediated apoptosis was associated with low protein expression of both bcl-2 and bcl-x, The level of CD95 cell-surface expression in melanoma cells was no indicator for CD95 sensitivity, Furthermore, FLIP protein was detectabl e in 7 out of the 11 cell lines, but showed no correlation to CD95 sensitiv ity. Certain cytokines have been described as modulating the susceptibility of tumor cells to CD95-induced cell death. Since IFN-alpha was proved to b e clinically efficient in melanoma therapy, we tested whether interferons h ave the ability to induce sensitivity to CD95 in primarily resistant melano ma cell lines. Here we show that IFN-gamma, but not IFN-a, is able to incre ase the susceptibility of sensitive cell lines and to induce CD95 sensitivi ty in resistant melanoma cell lines, accompanied by up-regulation of the pr otein expression level of CD95 and/or bcl-xS, Int, J, Cancer 82:727-736, 19 99. (C) 1999 Wiley-Liss, Inc.