Paclitaxel enhances tumoricidal potential of TRAIL via inhibition of MAPK in resistant gastric cancer cells

Li,Lin; Wen,Xian-Zi; Bu,Zhao-De; Cheng,Xiao-Jing; Xing,Xiao-Fang; Wang,Xiao-Hong; Zhang,Lian-Hai; Guo,Ting; Du,Hong; Hu,Ying; Fan,Biao; Ji,Jia-Fu

doi:10.3892/or.2016.4666

Paclitaxel enhances tumoricidal potential of TRAIL via inhibition of MAPK in resistant gastric cancer cells

Authors:
- Lin Li
- Xian-Zi Wen
- Zhao-De Bu
- Xiao-Jing Cheng
- Xiao-Fang Xing
- Xiao-Hong Wang
- Lian-Hai Zhang
- Ting Guo
- Hong Du
- Ying Hu
- Biao Fan
- Jia-Fu Ji
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Affiliations: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing, P.R. China, Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China, Department of Tissue Bank, Peking University Cancer Hospital and Institute, Beijing, P.R. China
Published online on: March 9, 2016 https://doi.org/10.3892/or.2016.4666
Pages: 3009-3017

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promise for cancer therapy due to its unique capacity to selectively trigger apoptosis in cancer cells. However, TRAIL therapy is greatly hampered by its resistance. A preclinical successful strategy is to identify combination treatments that sensitize resistant cancers to TRAIL. In the present study, we fully assessed TRAIL sensitivity in 9 gastric cancer cell lines. We found combined administration of paclitaxel (PTX) markedly enhanced TRAIL-induced apoptosis in resistant cancer cells both in vitro and in vivo. The sensitization to TRAIL was accompanied by activation of mitochondrial apoptotic pathway, upregulation of TRAIL receptors and downregulation of anti-apoptotic proteins including C-IAP1, C-IAP2, Livin and Mcl-1. Noticeably, we found PTX could suppress the activation of mitogen-activated protein kinases (MAPKs). Inhibition of MAPKs using specific inhibitors (ERK inhibitor U0126, JNK inhibitor SP600125 and P38 inhibitor SB202190) facilitated TRAIL-mediated apoptosis and cytotoxicity. Additionally, SP600125 upregulated TRAL receptors as well as downregulated C-IAP2 and Mcl-1 suggesting the anti-apoptotic role of JNK. Thus, PTX-induced suppression of MAPKs may contribute to restoring TRAIL senstitivity. Collectively, our comprehensive analyses gave new insight into the role of PTX on enhancing TRAIL sensitivity, and provided theoretical references on the development of combination treatment in TRAIL-resistant gastric cancer.

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