Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death

Srisuttee,Ratakorn; Koh,Sang  Seok; Park,Eun  Hee; Cho,Il-Rae; Min,Hye  Jin; Jhun,Byung  Hak; Yu,Dae-Yeul; Park,Sun; Park,Do  Yun; Lee,Mi  Ock; Castrillon,Diego  H.; Johnston,Randal  N.; Chung,Young-Hwa

doi:10.3892/ijmm.2011.699

August 2011 Volume 28 Issue 2

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August 2011 Volume 28 Issue 2

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Article

Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death

Authors:
- Ratakorn Srisuttee
- Sang Seok Koh
- Eun Hee Park
- Il-Rae Cho
- Hye Jin Min
- Byung Hak Jhun
- Dae-Yeul Yu
- Sun Park
- Do Yun Park
- Mi Ock Lee
- Diego H. Castrillon
- Randal N. Johnston
- Young-Hwa Chung
View Affiliations / Copyright

Affiliations: WCU Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, Republic of Korea, WCU Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-732, Republic of Korea
Pages: 255-260
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Published online on: May 11, 2011

https://doi.org/10.3892/ijmm.2011.699
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Abstract

The hepatitis B virus X (HBX) protein, a regulatory protein of the hepatitis B virus (HBV), has been shown to generate reactive oxygen species (ROS) in human liver cell lines; however, the mechanism by which cells protect themselves under this oxidative stress is poorly understood. Here, we show that HBX induces the up-regulation of Forkhead box class O 4 (Foxo4) not only in Chang cells stably expressing HBX (Chang-HBX) but also in primary hepatic tissues from HBX-transgenic mice. HBX also increased ROS, but reduction of the abundance of ROS using N-acetylcystein (NAC) diminished the levels of Foxo4. Elevated Foxo4 was also detected in nuclei of Chang-HBX cells but not in Chang cells stably expressing the vector (Chang-Vec), suggesting that HBX activates the transcriptional activity of Foxo4. When we examined whether HBX bypasses JNK signaling that targets Foxo4, we found that the activity of JNK but not of ERK is required for the up-regulation of Foxo4 even in the presence of HBX. Furthermore, the reduction of Foxo4 levels using siRNA or a JNK inhibitor rendered Chang-HBX cells sensitive to apoptosis under oxidative stress, suggesting that up-regulation of Foxo4 mediated by HBX enhances resistances to oxidative stress-induced cell death. Accordingly, we propose that Foxo4 may be a useful target for suppression in the treatment of HBV-associated hepatocellular carcinoma cells.

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death

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