title: Paclitaxel enhances tumoricidal potential of TRAIL via inhibition of MAPK in resistant gastric cancer cells.
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.
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xian-Zi
authors.initials: XZ
authors.lastname: Wen
authors.affiliation: Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Zhao-De
authors.initials: ZD
authors.lastname: Bu
authors.affiliation: 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.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Xing
authors.affiliation: Department of Tissue Bank, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wang
authors.affiliation: Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Lian-Hai
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Tissue Bank, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, P.R. China.
authors.forename: Biao
authors.initials: B
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Jia-Fu
authors.initials: JF
authors.lastname: Ji
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D020169:Caspases; D017239:Paclitaxel