Abstract
Expression of zinc-finger protein 143 (ZNF143), a human homolog of the Xenopus transcriptional activator protein Staf, is induced by various DNA-damaging agents including etoposide, doxorubicin, and gamma-irradiation. ZNF143 binds to cisplatin-modified DNA, and its levels are increased in cancer cells that are resistant to anticancer drugs, including cisplatin, suggesting that it plays a role in carcinogenesis and cancer cell survival. However, the mechanism of ZNF143 induction in cancer cells remains unclear. Both insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) have been reported to be overexpressed in cancer cells and to be related to anticancer drug resistance, but the identity of the relevant signaling mediators is still being investigated. In the present study, we observed that IGF-1 was able to induce ZNF143 expression in HCT116 human colon cancer cells and that wortmannin, an inhibitor of phosphatidylinositide 3- kinase (PI3-kinase), inhibited this induction, as did diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, and monodansylcardavarine (MDC), a receptor internalization inhibitor. Treatment with MDC decreased the IGF-1-stimulated generation of reactive oxygen species. Taken together, these data suggest that IGF-1 induces ZNF143 expression in cancer cells via PI3-kinase and reactive oxygen species generation during receptor internalization.
Highlights
Insulin-like growth factor-1 (IGF-1) is thought to regulate a variety of cellular processes, including cell survival, by binding to the IGF-1 receptor (IGF-1R) on cell surfaces
The induction of zinc-finger protein 143 (ZNF143) has been implicated in drug resistance, it remains to be elucidated how ZNF143 is induced in cancer cells and whether endogenous growth factors or cytokines in cancer cells might induce ZNF143 expression to enhance cell survival
IGF-1 was shown to protect against cisplatininduced cytotoxicity and to be involved in homologous recombination-directed DNA repair by regulating Rad51 localization (Trojanek et al, 2003), which made us hypothesize that IGF-1 may be one of growth factors to regulate ZNF143 expression in cancer cells to promote cancer cell survival
Summary
Insulin-like growth factor-1 (IGF-1) is thought to regulate a variety of cellular processes, including cell survival, by binding to the IGF-1 receptor (IGF-1R) on cell surfaces. (B, D) Cells were grown and serum-starved as in (A), incubated with IGF-1 (100 ng/ml) for the indicated lengths of time, lysed, and analyzed for ZNF143 expression by immunoblotting (B) or RT-PCR (D). We investigated the possibility that IGF-1 treatment would induce ZNF143 expression in cancer cells and sought to identify the possible mediators of this induction.
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