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Trichostatin A potentiates TRAIL-induced antitumor effects via inhibition of ERK/FOXM1 pathway in gastric cancer

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Tumor Biology

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal apoptosis inducer and believed to have promise in cancer therapy, yet part of cancer cells exhibit resistance to TRAIL-mediated apoptosis. This necessitates the exploration of agents that resensitizes cancer cells to TRAIL. In our study, we found that Trichostatin A (TSA), an histone deacetylase (HDAC) inhibitor, augmented TRAIL-induced apoptosis in gastric cancer cells in a caspase-dependent manner. Besides, upregulation of DR5 and downregulation of anti-apoptotic proteins including XIAP, Mcl-1, Bcl-2 and Survivin also contributed to this synergism. Noticeably, TSA treatment inhibited Forkhead boxM1 (FOXM1), which expression level showed negative correlation with TRAIL sensitivity. Similarly, silencing of FOXM1 by small interfering RNA (siRNA) resensitized cancer cells to TRAIL and strengthened the TRAIL-augmenting effect of TSA. In addition, we demonstrated the depletion of FOXM1 was a consequence of the inactivation of ERK mediated by TSA. Collectively, it was first shown that TSA potentiated TRAIL sensitivity via ERK/FOXM1 pathway in gastric cancer cells. FOXM1 might serve as a biomarker for predicting sensitivity to TRAIL.

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Acknowledgments

This work was supported in part by the National Nature Science Foundation of China (No. 81402308, No.81301874), the Natural Science Foundation of Beijing (No.7132051), 985 special project sponsored by Peking University Health Science Center (No.2013-5-09), and the Ministry of Science and Technology of the People’s Republic of China (No. 2014AA020603).

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Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China

    Lin Li, Xiao-Fang Xing, Xiao-Jing Cheng, Ting Guo, Hong Du, Xian-Zi Wen & Jia-Fu Ji

  2. Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute Beijing, #52 Fu-Cheng Road, Hai-Dian District, Beijing, 100142, China

    Lin Li, Biao Fan, Lian-Hai Zhang & Jia-Fu Ji

  3. The Tissue Bank, Peking University Cancer Hospital & Institute, Fu-Cheng Road, Beijing, China

    Lian-Hai Zhang & Xiao-Hong Wang

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  1. Lin Li
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Li, L., Fan, B., Zhang, LH. et al. Trichostatin A potentiates TRAIL-induced antitumor effects via inhibition of ERK/FOXM1 pathway in gastric cancer. Tumor Biol. 37, 10269–10278 (2016). https://doi.org/10.1007/s13277-016-4816-5

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  • DOI: https://doi.org/10.1007/s13277-016-4816-5

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