Overexpression of metallothionein confers resistance to the cytotoxic effect of TNF with cadmium in MCF-7 breast carcinoma cells.

Experiments were designed to determine whether cells that overexpress metallothionein acquire resistance to the cytotoxic action of tumor necrosis factor (TNF). Human MCF-7 mammary carcinoma cells, which are sensitive to the cytotoxic action of TNF, were stably transfected with a vector in which the human metallothionein-IIA (hMT-IIA) gene was placed under the control of the constitutively active beta-actin promoter. MT-expressing clones displayed greater resistance to cadmium toxicity than control cell lines. Neither control-transfected nor MT-expressing cell lines were sensitive to the cytotoxic effect of TNF alone, even at concentrations as high as 200 ng/ml. However, treatment of control-transfected cells with TNF in the presence of CdCl2 produced a greater cytotoxic effect than CdCl2 alone. MT-expressing cell clones were protected from this synergistic cytotoxic effect of TNF and CdCl2. These results suggest that under certain conditions MT expression may protect tumor cells from the cytotoxic effects of TNF.