Journal Article

Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway

Wei Qu, Carl D. Bortner, Teruaki Sakurai, Michael J. Hobson and Michael P. Waalkes

in Carcinogenesis

Volume 23, issue 1, pages 151-159
Published in print January 2002 | ISSN: 0143-3334
Published online January 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.1.151
Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway

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This study examined the role of signal transduction and apoptosis in malignant transformation induced by arsenic. Prior study showed that chronic arsenite exposure (500 nM, │18 weeks) induced malignant transformation in rat liver TRL 1215 cells. In the present work, these transformed cells were compared with passage-matched control cells. In addition, TRL 1215 cells were treated subchronically (up to 6 weeks) with arsenic (termed pre-transformed cells) to define events occurring prior to arsenic-induced transformation. Flow cytometry using annexin/FITC revealed that arsenic-induced apoptosis in transformed cells was markedly suppressed in comparison to control or pre-transformed cells. Ro318220, a strong activator of JNK, enhanced arsenite-induced apoptosis in transformed cells. Densitometric analysis of western blots revealed that the ratios of both Bcl-xL/Bax and Bcl-2/Bax were significantly increased (>2.5-fold) in arsenic-transformed cells. Transformed, pre-transformed and control cells were treated with arsenic and levels of phosphorylated extracellular signal-regulated kinases, ERK1/2, JNK1/2 and p38 were determined by western blot analysis. The three mitogen-activated protein kinases (MAPKs) were phosphorylated in a dose-dependent fashion in all cell types. However, the levels of phosphorylated JNK1/2 were markedly decreased in the arsenic-transformed cells, whereas in pre-transformed cells the levels of phosphorylated MAPKs remained the same as in control cells. JNK kinase activity was suppressed in transformed cells whereas Ro318220 enhanced this activity. Thus, during arsenic-induced malignant transformation resistance to apoptosis develops, possibly due to perturbation of the JNK pathway.

Keywords: As+3, arsenite the trivalent form of arsenic; EGF, epidermal growth factor; ERK1/2, extracellular signal-regulated kinases1/2; JNK1/2, c-Jun NH2-terminal kinase1/2; MAPKs, mitogen-activated protein kinases; MKP-1, mitogen-activated protein kinase phosphatase-1; PKC, protein kinase C; TRL 1215, a rat liver epithelial cell line; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end-labeling.

Journal Article.  6981 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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