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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.

Authors
Joseph-P; Muchnok-TK; Klishis-ML; Roberts-JR; Antonini-JM; Whong-WZ; Ong-T
Source
Toxicol Sci 2001 Jun; 61(2):295-303
NIOSHTIC No.
20021345
Abstract
The molecular mechanisms of carcinogenesis by cadmium were studied using BALB/c-3T3 cell transformation and nude mouse tumorigenesis models. BALB/c-3T3 cells transformed with cadmium chloride were subcutaneously injected into nude mice to develop tumors and the cell lines derived from these tumors were used in the present study. The proto-oncogenes c-fos and c-jun were overexpressed in 100% (10 out of 10) of the cell lines, while a statistically significant overexpression of c-myc was observed in 40% (4 out of 10) of the cell lines. Analysis of tumor cells stained with fluorescent dyes specific for reactive oxygen species revealed that these cells possessed markedly higher levels of superoxide anion and hydrogen peroxide compared with the nontransformed cells. Similarly, the intracellular calcium level was higher in the tumor cells compared with the nontransformed cells. Overexpression of the proto-oncogenes in these cells was blocked by treating the cells with superoxide dismutase, catalase, and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetra acetoxy methyl ester (BAPTA/AM), which are scavengers of superoxide anion, hydrogen peroxide, and calcium, respectively. This confirmed that the overexpression of the proto-oncogenes in the tumor cells required elevated intracellular levels of reactive oxygen species and calcium. In addition to the scavengers of reactive oxygen species and calcium, inhibitors specific for transcription (actinomycin D), protein kinase C (RO-31-8220), and MAP kinase (PD 98059) also blocked the cadmium-induced overexpression of the proto-oncogenes in the tumor cells. Exposure of the nontransformed BALB/c-3T3 cells to 20 microM cadmium chloride for 1 h caused elevated intracellular levels of superoxide anion, hydrogen peroxide, and calcium, 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 nontransformed cells with the various modulators prior to their exposure to cadmium chloride resulted in inhibition in the expression of the proto-oncogenes. Based on these data, we conclude that the cadmium-induced overexpression of cellular proto-oncogenes is mediated by the elevation of intracellular levels of superoxide anion, hydrogen peroxide, and calcium. Further, the cadmium-induced overexpression of the proto-oncogenes is dependent on transcriptional activation as well as on pathways involving protein kinase C and MAP kinase.
Keywords
Cadmium-compounds; Cell-transformation; Carcinogenesis; Calcium-compounds; Tumors; Animal-studies; Laboratory-animals; Tumorigens; Tumorigenesis; Oncogenic-agents; Carcinogens; Carcinogenicity; Animals
Contact
Pius Joseph, MS 3014, Toxicology and Molecular Biology Branch, CDC/NIOSH, 1095 Willowdale Road, Morgantown, WV 26505
CODEN
TOSCF2
CAS No.
7440-43-9; 7440-70-2
Publication Date
20010601
Document Type
Journal Article
Email Address
pcj5@cdc.gov
Fiscal Year
2001
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
1096-6080
NIOSH Division
HELD
Source Name
Toxicological Sciences
State
WV
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