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 HT1080LUC experimental 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.
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Acknowledgements
The study was supported by Grants from the National Natural Science Foundation of China (81373437 and 81321004) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-12M-02-002).
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The animal study was performed under approval of the Committee on the Ethics of Animal Experiments of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences (IMBF20060302). The study protocols were carried out according to the recommendations in the Regulation for the Management of Laboratory Animals of the Ministry of Science and Technology of China.
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There is no conflict of interest declared by the authors.
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Wang, X., Qiao, X., Shang, Y. et al. RGD and NGR modified TRAIL protein exhibited potent anti-metastasis effects on TRAIL-insensitive cancer cells in vitro and in vivo. Amino Acids 49, 931–941 (2017). https://doi.org/10.1007/s00726-017-2395-4
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DOI: https://doi.org/10.1007/s00726-017-2395-4