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Cadmium‐induced malignant transformation in rat liver cells: Role of aberrant oncogene expression and minimal role of oxidative stress
Author(s) -
Qu Wei,
Diwan Bhalchandra A.,
Reece Jeffrey M.,
Bortner Carl D.,
Pi Jingbo,
Liu Jie,
Waalkes Michael P.
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20736
Subject(s) - malignant transformation , oxidative stress , reactive oxygen species , oncogene , biology , cadmium , cell culture , microbiology and biotechnology , cancer research , cell , chemistry , endocrinology , cell cycle , biochemistry , genetics , organic chemistry
Our study examined the role of oxidative stress and aberrant gene expression in malignant transformation induced by chronic, low‐level cadmium exposure in non‐tumorigenic rat liver epithelial cell line, TRL 1215. Cells were cultured in 1.0 μM cadmium (as CdCl 2 ) for up to 28 weeks and compared to passage‐matched control cells. The level of cadmium used for transformation produced no evidence of increased superoxide (O 2 − · ) or hydrogen peroxide (H 2 O 2 ) levels in the early stages of exposure (≤24 hr). The chronic cadmium exposed liver epithelial cells (CCE‐LE) were hyperproliferative with a growth rate about 3‐fold higher than control cells. CCE‐LE cells produced highly aggressive tumors upon inoculation into mice confirming malignant transformation. Analysis of cellular reactive oxygen species (ROS) showed that CCE‐LE cells possessed markedly lower basal levels of intracellular O 2 − · and H 2 O 2 and were very tolerant to high‐dose (50 μM) cadmium‐induced ROS. Time course studies showed the production of ROS by high‐dose cadmium was abolished well in advance of malignant transformation. In contrast, marked overexpression of the oncogenes c‐ myc and c‐ jun occurred in transformed CCE‐LE cells as evidenced by up to 10‐fold increases in both transcript and protein. A significant increase in DNA‐binding activity of the transcription factors AP‐1 and NF‐κB occurred in CCE‐LE cells. Increases in oncogene expression and transcription factor activity occurred concurrently with malignant transformation. Thus, cadmium‐induced ROS occurs as an early, high‐dose event but is abolished well in advance of malignant transformation. Low‐level chronic cadmium triggers oncogene overexpression possibly by altering critical transcription factor activity. Such changes in cellular gene expression likely culminate in the loss of growth control and cadmium‐induced neoplastic transformation in CCE‐LE cells, whereas generation of ROS by cadmium seemed to play a minimal role in this transformation. © 2004 Wiley‐Liss, Inc.