Carcinogenesis Advance Access originally published online on August 6, 2008
Carcinogenesis 2008 29(11):2045-2052; doi:10.1093/carcin/bgn184
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The forkhead transcription factor FOXO4 sensitizes cancer cells to doxorubicin-mediated cytotoxicity
Institute of Toxicology, Heinrich Heine University of Düsseldorf, PO Box 10 10 07, D-40001 Düsseldorf, Germany
1 Molecular Toxicology, Institut für Umweltmedizinische Forschung, PO Box 10 30 45, D-40021 Düsseldorf, Germany
* To whom correspondence should be addressed. Tel: +49 211 8113001; Fax: +49 211 8113013; Email: chovolou{at}uni-duesseldorf.de
The forkhead superfamily of transcription factors, which play major roles in control of cellular proliferation, oxidative stress and apoptosis, are becoming more and more considered as crucial therapeutic targets in cancer. In this study, we addressed the contribution of class O of forkhead box transcription factor (FOXO) 4 transcription factor, a forkhead superfamily member, to cytotoxicity mediated by the anthracyclic drug doxorubicin. FOXO4 can be phosphorylated by phosphatidylinositol-3-kinase/AKT signaling resulting in its inactivation and nuclear exclusion. Under stress conditions, FOXO4 can be phosphorylated via jun N-terminal kinase (JNK) leading to increased transcriptional activation of the transcription factor. Our results show that doxorubicin incubation led to phosphorylation of AKT and concomitantly to AKT-dependent inactivation and nuclear exclusion of the tumor suppressor FOXO4 in Hct-116 cells. We found that inhibition of FOXO4 nuclear exclusion by blockage of AKT phosphorylation following overexpression of dominant-negative AKT enhanced doxorubicin-mediated cytotoxicity. Overexpression of wild-type FOXO4 led to an increase in doxorubicin-mediated cytotoxicity, which was further exacerbated by overexpression of a solely nuclear-localized FOXO4 mutant. In contrast, though doxorubicin resulted in JNK activation, modulation of JNK-dependent regulation of FOXO4 was of no effect to doxorubicin cytotoxicity. These results show for the first time that in Hct-116 cells sustained nuclear localization of FOXO4 seems to be one crucial point enhancing doxorubicin-induced cytotoxicity and apoptosis. Targeting FOXO4 or AKT may lead to new chances in sensitizing cancer cells to cytostatic drugs thereby allowing use of lower drug concentrations and minimizing drug-induced adverse effects in patients.
Abbreviations: DN-AKT, dominant-negative AKT; EC50, the half maximal effective concentration values; FOXO, class O of forkhead box transcription factor; HA, hemaglutinin; JNK, jun N-terminal kinase; MTT, 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide; PCR, polymerase chain reaction; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homologue; ROS, reactive oxygen species; SEAP, secreted embryonic alkaline phosphatase
Received February 25, 2008; revised July 4, 2008; accepted August 3, 2008.
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