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LIGHT is a new member of the tumor necrosis factor superfamily, which binds to lymphotoxin β receptor, herpes virus entry mediator, or TR6. This work was carried out to elucidate the molecular mechanism of LIGHT-sensitized, interferon gamma (IFNγ)-mediated apoptosis of MDA-MB-231 cells. It was revealed that LIGHT treatment resulted in down-regulation of anti-apoptosis Bcl-2 family member: Bcl-2, Bcl-XL, Bag-1, and Mcl-1; up-regulation of pro-apoptosis Bcl-2 family member: Bak and Ser (112)-phosphor-Bad; down-regulation of pro-apoptosis Bcl-2 member Bax; the other pro-apoptosis member Bid remains unaltered. LIGHT treatment also resulted in activation of caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, DFF45, and PARP. However, caspase activation and caspase activity, especially caspase-3 activity, is not required for LIGHT-induced apoptosis of MDA-MB-231 cells, since caspase-3 inhibitor, benzyloxycarbonyl–Asp–Glu–Val–Asp-fluoromethylketone, and a broad range caspase inhibitor, benzyloxycarbonyl–val–ala–asp–fluoromethylketone failed to block the apoptosis induced by LIGHT and IFNγ in MDA-MB-231 cells. In summary, LIGHT-sensitized IFNγ-mediated apoptosis of MDA-MB-231 cells is probably through down-regulation of anti-apoptosis Bcl-2 family members; it could be caspase (especially caspase-3)-independent, even though extensive caspase activation was observed. [Copyright &y& Elsevier]