Activating transcription factor 4 increases chemotherapeutics resistance of human hepatocellular carcinoma.

Abstract

It has been reported that activating transcription factor 4 (ATF4) increases the processes of tumor growth, metastasis and drug resistance. However, the role played by ATF4 in chemoresistance of hepatocellular carcinoma (HCC) remains unknown. Clarification of this role of ATF4 in HCC could greatly benefit the efficacy of clinical treatment of HCC. In this study, we found that ATF4 was overexpressed in about 50.7% of HCC tissues. In fact knockdown of ATF4 significantly increased the cytotoxicity of cisplatin in both in vitro and in vivo assays, while overexpression of this molecule dramatically decreased the sensitivity of HCC cell lines to cisplatin. Additionally, we found that synthesis of glutathione was significantly reduced in HCC cell lines subjected to ATF4 knockdown. Taken together, these results demonstrate that ATF4 can increase resistance to cisplatin in HCC by increased biosynthesis of glutathione, and that this may be a potent novel target for the future development of anti-HCC drugs.

• Authors: Zhuhong Zhang, Jing Yin, Chunyan Zhang, Ning Liang, Nan Bai, Antao Chang, Yanhua Liu, Zongjin Li, Xiaoyue Tan, Na Li, Dan Lv, Rong Xiang, Yaping Tian, Chenghu Liu
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 13 Issue 6 Pg. 435-42 (Apr 2012) ISSN: 1555-8576 [Electronic] United States
• PMID: 22338651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF4 protein, human
• Antineoplastic Agents
• Activating Transcription Factor 4
• Glutathione
• Cisplatin

Topics

• Activating Transcription Factor 4 (genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology)
• Base Sequence
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• Gene Knockdown Techniques
• Glutathione (metabolism)
• Humans
• Liver (metabolism)
• Liver Neoplasms (drug therapy, metabolism)
• Mice
• Mice, SCID
• Molecular Sequence Data
• Reference Values
• Xenograft Model Antitumor Assays