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Research Paper
Inhibiting Survivin Expression Enhances TRAIL-Induced Tumoricidal Activity in Human Hepatocellular Carcinoma via Cell Cycle Arrest
Song-Qing He, Hasibur Rehman, Ming-guang Gong, Yong-Zhong Zhao, Zhi-Yong Huang, Chang-Hai Li, Wan-Guang Zhang and Xiao-Ping Chen
volume 6 | issue 8
August 2007Pages: 1247 - 1257
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Human Hepatocellular carcinoma (HCC) cell types exhibit a major resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death, and the key determinants of mechanisms accounting for TRAIL susceptibility, still remain controversial. Our previous studies showed that overexpression of survivin reduced sensitivity of HCC cells to TRAIL. The aim of this study is to investigate how tumor cells escape TRAIL-mediated surveillance through survivin expression and how to reverse the resistance of TRAIL-inducing apoptosis. Seven tumor cell lines were treated with or without TRAIL protein and antisense oligodeoxynucleotides (ODNs) against survivin in culture. HepG2 and SMMC7721 cells were treated with mimosine, thymidine or nocodazole to synchronize their cell cycle phases and then used to test their sensitivity to TRAIL. In vivo effects of TRAIL plasmid alone or in combination with survivin antisense ODNs on tumor growth were evaluated in a nude mouse hepatoma model of HepG2 cell grafts. Varied levels of survivin mRNA in various cell lines were evaluated and negatively correlated to TRAIL-induced apoptosis. Hepatoma HepG2 and SMMC7721 cells in G1 or S phase are more sensitive to TRAIL than those in G2 phase. Treatment with survivin antisense ODNs caused S phase arrest and significantly enhanced TRAIL-induced apoptosis. TRAIL protein caused G2/M arrest and resulted in an increase of survivin in HepG2 cells. Combined TRAIL plasmid and survivin antisense ODNs significantly supressed the growth of tumor xenografts as compared to TRAIL plamid or antisense ODNs alone during a 4-week of observation. The findings indicate that survivin may play a role in tumor cell resistance to TRAIL-induced apoptosis, at least in part, through cell cycle regulation. Manipulation of survivin expression levels may sensitizes tumor cells to TRAIL-induced apoptosis.
Authors
Song-Qing He
Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
Hasibur Rehman
Jamia Hamdard, New Delhi, India
Ming-guang Gong
Tongji Medical College,Huazhong University of Science and Technology, Wuhan, P.R. China
Yong-Zhong Zhao
Guilin Medical College Affiliated Hospital, Guilin, P.R. China
Zhi-Yong Huang
Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
Chang-Hai Li
Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
Wan-Guang Zhang
Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
Xiao-Ping Chen
Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.