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 β-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.