Cadmium Produces a Delayed Mitogenic Response and Modulates the EGF Response in Quiescent NRK Cells

Recent studies have shown that cadmium, at subtoxic levels, may induce a response characteristic of that elicited by a type of growth factor that supports the anchorage independent growth of cells that are not fully transformed. That is, Cd++ was found to replace transforming growth factor beta in supporting soft agar growth of NRK-49F cells. To test the extent to which Cd++ further mimics transforming growth factor beta in its effects and to establish response patterns that suggest possible molecular mechanisms of action, we have determined the effects of Cd++ and/or epidermal growth factor (EGF) on DNA synthesis in quiescent NRK-49F cells. We found that subtoxic doses of Cd++ modulate EGF-induced DNA synthesis in a dose-dependent fashion. Although Cd++ effects on early (16-24 hr) EGF-induced DNA synthesis are primarily inhibitory, later effects involve stimulation as well. Subtoxic doses of Cd++ did not stimulate DNA synthesis in quiescent cells within 24 hr of addition. At later times (40 or 64 hr), however, an increase in DNA synthesis of up to threefold was induced by 0.25 microM Cd++. This pattern of mitogenic response, involving inhibition of early growth-factor induced DNA synthesis and stimulation of late DNA synthesis, is consistent with that reported to be effected in some instances by transforming growth factor beta. Because a defined pattern of gene expression also is associated with the mitogenic responses to transforming growth factor beta, future studies at the molecular level can definitively test the degree to which Cd++ and transforming growth factor beta effects are common.