title: RGD and NGR modified TRAIL protein exhibited potent anti-metastasis effects on TRAIL-insensitive cancer cells in vitro and in vivo.
abstract: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered to be a promising anti-tumor agent since the discovery of TRAIL-mediated apoptosis specifically on cancer cells. However, TRAIL resistance of tumor cells and patients remains to be an insurmountable obstacle for its clinical application. Here, we expressed TRAIL-related recombinant protein RGD-TRAIL, TRAIL-NGR, and RGD-TRAIL-NGR by fusing tumor targeting peptides RGD and (or) NGR at the N-terminus and C-terminus, respectively, to not only induce apoptosis of cancer cells but also inhibit metastasis. The fusion proteins possessed potent cytotoxicity with approximative IC50 in H460 and A549 cells, while TRAIL-NGR and RGD-TRAIL-NGR appeared to be more effective in HT1080 and PANC-1 cells which were relatively insensitive to TRAIL. A low concentration of fusion proteins, especially RGD-TRAIL-NGR, could inhibit migration of A549 and HT1080 cells in vitro and lung metastasis in HT1080LUCexperimental model in vivo, indicating that the recombinant protein maintained the function of both TRAIL and targeting peptide RGD and NGR, which improved the sensitivity of tumor cells to TRAIL.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Qiao
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: He
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. bjcsz@imb.pumc.edu.cn.
authors.forename: Shu-Zhen
authors.initials: SZ
authors.lastname: Chen
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003001:Cloning, Molecular; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000235:genetics* / Q000378:metabolism; D010843:Pichia / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C526428:NGR peptide; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C047981:arginyl-glycyl-aspartic acid
keywords: Apoptosis; Fusion protein; Migration; NGR; RGD; TRAIL