Lithium sensitizes tumor cells in an NF-kappa B-independent way to caspaseactivation and apoptosis induced by tumor necrosis factor (TNF) - Evidencefor a role of the TNF receptor-associated death domain protein

We have previously shown that lithium salts can considerably increase the d irect cytotoxic effect of tumor necrosis factor (TNF) on various tumor cell s in vitro and in vivo. However, the underlying mechanism has remained larg ely unknown. Here we show that the TNF-sensitizing effect of lithium chlori de (LiCl) is independent of the type of cell death, either necrosis or apop tosis. In the case of apoptosis, TNF-lithium synergism is associated with a n enhanced activation of caspases and mitochondrial cytochrome c release. S ensitization to apoptosis is specific for TNF-induced apoptosis, whereas Fa s-mediated or etoposide-induced apoptosis remains unaffected. LiCl also pot entiates cell death induced by artificial oligomerization of a fusion prote in between FKBP and the TNF receptor-associated death domain protein. TNF-i nduced activation of NF-KB-dependent gene expression is not modulated by Li Cl treatment. These results indicate that LiCl enhances TNF-induced cell de ath in an NF-KB-independent way, and suggest that the TNF receptor-associat ed death domain protein plays a crucial role in the TNF-sensitizing effect of LiCl.