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

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics


Show Summary Details


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

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.