Cadmium-induced cell transformation and tumorigenesis are associated with transcriptional activation of c-fos, c-jun and c-myc proto-oncogenes: role of cellular calcium and reactive oxygen species.
Joseph-P; Muchnok-TK; Klishis-ML; Roberts-JR; Antonini-JM; Whong-WZ; Ong-T
Toxicologist 2001 Mar; 60(1):31
The molecular mechanisms of cell transformation induced by cadmium (Cd) were studied using BALB/c-3T3 cell transformation and nude mouse tumorigenesis models. BALB/c-3T3 cells transformed with CdCl2 were subcutaneously injected into nude mice to develop tumors and the cell lines derived from these tumors were used in this study. The proto-oncogenes c-fos, c-jun, and c-myc were overexpressed in the cell lines. Tumor cells stained with fluorescent dyes specific for reactive oxygen species (ROS) revealed that these cells possessed markedly higher levels of superoxide anion and hydrogen peroxide compared with the nontransformed cells. Similarly, the intracellular calcium (Ca) level was higher in the tumor cells compared with the nontransformed cells. Overexpression of the proto-oncogenes in these cells was blocked by superoxide dismutase, catalase and BAPTA/AM confirming that the overexpression of the proto-oncogenes in the tumor cells required elevated levels of ROS and Ca. Inhibitors specific for transcription, PKC and MAP kinase also blocked the overexpression of the proto-oncogenes in the tumor cells. Exposure of the nontransformed BALB/c-3T3 cells to CdCl2 for 1 hr caused elevated intracellular levels of superoxide anion, hydrogen peroxide and Ca with corresponding increases in the expression levels of c-fos; c-jun and c-myc. As in the case of the tumor cells, treating the non-transformed cells with the various modulators prior to their exposure to CdCl2 resulted in inhibition in the expression of the proto-oncogenes. Based on these data; we conclude that the Cd-induced overexpression of cellular proto-oncogenes is mediated by the elevation of intracellular levels of superoxide anion, hydrogen peroxide and Ca. Further, the Cd-induced overexpression of the proto-oncogenes is dependent on transcriptional activation as well as on pathways involving PKC and MAP kinase.
Cadmium-compounds; Calcium-compounds; Cell-transformation; Oncogenesis; Oncogenic-agents; Oncogenicity; Tumorigenesis; Tumorigens; Tumors; Laboratory-animals; Animals; Animal-studies; Models
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California