Abstract
We have previously shown that lithium salts can considerably increase the direct cytotoxic effect of tumor necrosis factor (TNF) on various tumor cells in vitro and in vivo. However, the underlying mechanism has remained largely unknown. Here we show that the TNF-sensitizing effect of lithium chloride (LiCl) is independent of the type of cell death, either necrosis or apoptosis. In the case of apoptosis, TNF/lithium synergism is associated with an enhanced activation of caspases and mitochondrial cytochrome c release. Sensitization to apoptosis is specific for TNF-induced apoptosis, whereas Fas-mediated or etoposide-induced apoptosis remains unaffected. LiCl also potentiates cell death induced by artificial oligomerization of a fusion protein between FKBP and the TNF receptor-associated death domain protein. TNF-induced activation of NF-kappa B-dependent gene expression is not modulated by LiCl treatment. These results indicate that LiCl enhances TNF-induced cell death in an NF-kappa B-independent way, and suggest that the TNF receptor-associated death domain protein plays a crucial role in the TNF-sensitizing effect of LiCl.
Highlights
We have previously shown that lithium salts can considerably increase the direct cytotoxic effect of tumor necrosis factor (TNF) on various tumor cells in vitro and in vivo
These results indicate that lithium chloride (LiCl) enhances TNFinduced cell death in an NF-B-independent way, and suggest that the TNF receptor-associated death domain protein plays a crucial role in the TNF-sensitizing effect of LiCl
The TNF-sensitizing Effect of LiCl Is Independent of the Type of Cell Death—To investigate whether the TNF/LiCl synergism depends on the type of cell death, we analyzed the effect of LiCl on TNF-induced killing of L929 and KYM37E4 cells
Summary
We have previously shown that lithium salts can considerably increase the direct cytotoxic effect of tumor necrosis factor (TNF) on various tumor cells in vitro and in vivo. Many cell types respond to TNF by the expression of specific proteins, including other cytokines, adhesion proteins, and enzymes induced in the production of proinflammatory mediators [1] These proinflammatory effects of TNF lead to several toxic side effects in vivo after injection of high TNF doses [4]. Sensitization by Lithium of Tumor Cells question of how an apoptotic stimulus is linked to the activation of caspases has been partially answered by the isolation of caspase-8 [13, 14] This protein associates through its prodomain with the Fas-associated death domain (FADD), which is a component of the p55 TNF-R (TNF-RI) and the Fas receptor complex. Inhibition of NF-B-dependent gene expression has recently been shown to sensitize cancer cells to TNF-induced apoptosis [21]
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