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Bortezomib Synergizes TRAIL-Induced Apoptosis in Gastric Cancer Cells

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Abstract

Background/Aims

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a newly identified biological agent has shown promising antitumor effects in a wide range of cancers. However, gastric cancer cells are less sensitive than other cancer cells to TRAIL-induced apoptosis. Here, we combined TRAIL with bortezomib, a proteasomal inhibitor to induce apoptosis in three gastric cancer cell lines.

Methods

After the cells were treated with TRAIL and/or bortezomib, the cell viability, apoptosis and cell cycle distribution were examined. The levels of death receptors and the mitochondrial membrane potential were also detected. The expression of apoptosis-associated proteins was determined by Western blot.

Results

Bortezomib at low concentration significantly (P < 0.05) enhanced the cytotoxic effect of TRAIL by enhancing apoptosis as well as cell cycle arrest at G2/M phase. The enhancement of efficiency of TRAIL by bortezomib involved up-regulation of death receptor 4 and 5, as well as reduction of the mitochondrial membrane potential. Further study showed that combined treatment with TRAIL and bortezomib down-regulated anti-apoptotic protein cIAP-1, and over expression of cIAP-1 significantly (P < 0.05) reduced the synergistic effect between TRAIL and bortezomib.

Conclusions

Bortezomib synergizes TRAIL-induced apoptosis in human gastric cancer cells. The synergistic effect between these two drugs is associated with up-regulation of death receptors and down-regulation of cIAP-1. The combination of TRAIL and bortezomib might be an effective regimen for the treatment of advanced gastric cancer.

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Acknowledgments

We thank Dr. Ashwell (National Institutes of Health, USA) for kindly providing the Flag-tagged cIAP-1-expressing pCMVTag 2B plasmid. This work was supported by: Chinese National Foundation of National Sciences grants 30770993; Liaoning Province Foundation of National Sciences grants 20072100; China Postdoctor Foundation of Science grants 20070411081.

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Authors and Affiliations

  1. Department of Medical Oncology, The First Hospital of China Medical University, 110001, Shenyang, People’s Republic of China

    Jing Liu, Xiu-Juan Qu, Ling Xu, Ye Zang, Jing-Lei Qu, Ke-Zuo Hou & Yun-Peng Liu

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  1. Jing Liu
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  2. Xiu-Juan Qu
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  3. Ling Xu
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  4. Ye Zang
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Correspondence to Yun-Peng Liu.

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Liu, J., Qu, XJ., Xu, L. et al. Bortezomib Synergizes TRAIL-Induced Apoptosis in Gastric Cancer Cells. Dig Dis Sci 55, 3361–3368 (2010). https://doi.org/10.1007/s10620-010-1191-8

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  • DOI: https://doi.org/10.1007/s10620-010-1191-8

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