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A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth
Pancreatic cancer is one of the most lethal human diseases, with an all-stage 5-year survival rate below 5%. To date, no effective and specific therapy is available for this disease. Mutations in KRAS are frequently reported in pancreatic and many other cancers; thus, KRAS is an attractive therapeut...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190097/ https://www.ncbi.nlm.nih.gov/pubmed/27322423 http://dx.doi.org/10.18632/oncotarget.9996 |
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author | Pan, Ting Zhang, Yiwen Zhou, Nan He, Xin Chen, Cancan Liang, Liting Duan, Xiaobing Lin, Yingtong Wu, Kang Zhang, Hui |
author_facet | Pan, Ting Zhang, Yiwen Zhou, Nan He, Xin Chen, Cancan Liang, Liting Duan, Xiaobing Lin, Yingtong Wu, Kang Zhang, Hui |
author_sort | Pan, Ting |
collection | PubMed |
description | Pancreatic cancer is one of the most lethal human diseases, with an all-stage 5-year survival rate below 5%. To date, no effective and specific therapy is available for this disease. Mutations in KRAS are frequently reported in pancreatic and many other cancers; thus, KRAS is an attractive therapeutic target. Our objective was to specifically eliminate mutant KRAS and induce cell death of tumors expressing this mutant protein. We thus constructed several chimeric proteins by connecting the C-terminal domains of several adaptor proteins of E3 ubiquitin ligases such as CBL, CHIP, E6AP, and VHL, as well as VIF encoded by human immunodeficiency virus type 1 (HIV-1), to the Ras binding domain (RBD) of Raf. Although all of these chimeric proteins caused the degradation of mutant KRAS and the death of KRAS-mutant-tumor cell lines, the RBD-VIF with a protein transduction domain (PTD), named PTD-RBD-VIF, had the strongest tumor-killing effect. Intraperitoneally administered recombinant PTD-RBD-VIF potently inhibited the growth of xenografted KRAS-mutant pancreatic cancer cells. Our findings indicate that recombinant PTD-RBD-VIF, a chimeric protein with a combined cellular-viral origin, could be further developed for the treatment of various tumors harboring mutant or over-activated KRAS, especially for cases presenting with pancreatic cancer recurrence after surgery. |
format | Online Article Text |
id | pubmed-5190097 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-51900972017-01-05 A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth Pan, Ting Zhang, Yiwen Zhou, Nan He, Xin Chen, Cancan Liang, Liting Duan, Xiaobing Lin, Yingtong Wu, Kang Zhang, Hui Oncotarget Research Paper Pancreatic cancer is one of the most lethal human diseases, with an all-stage 5-year survival rate below 5%. To date, no effective and specific therapy is available for this disease. Mutations in KRAS are frequently reported in pancreatic and many other cancers; thus, KRAS is an attractive therapeutic target. Our objective was to specifically eliminate mutant KRAS and induce cell death of tumors expressing this mutant protein. We thus constructed several chimeric proteins by connecting the C-terminal domains of several adaptor proteins of E3 ubiquitin ligases such as CBL, CHIP, E6AP, and VHL, as well as VIF encoded by human immunodeficiency virus type 1 (HIV-1), to the Ras binding domain (RBD) of Raf. Although all of these chimeric proteins caused the degradation of mutant KRAS and the death of KRAS-mutant-tumor cell lines, the RBD-VIF with a protein transduction domain (PTD), named PTD-RBD-VIF, had the strongest tumor-killing effect. Intraperitoneally administered recombinant PTD-RBD-VIF potently inhibited the growth of xenografted KRAS-mutant pancreatic cancer cells. Our findings indicate that recombinant PTD-RBD-VIF, a chimeric protein with a combined cellular-viral origin, could be further developed for the treatment of various tumors harboring mutant or over-activated KRAS, especially for cases presenting with pancreatic cancer recurrence after surgery. Impact Journals LLC 2016-06-14 /pmc/articles/PMC5190097/ /pubmed/27322423 http://dx.doi.org/10.18632/oncotarget.9996 Text en Copyright: © 2016 Pan et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Pan, Ting Zhang, Yiwen Zhou, Nan He, Xin Chen, Cancan Liang, Liting Duan, Xiaobing Lin, Yingtong Wu, Kang Zhang, Hui A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth |
title | A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth |
title_full | A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth |
title_fullStr | A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth |
title_full_unstemmed | A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth |
title_short | A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth |
title_sort | recombinant chimeric protein specifically induces mutant kras degradation and potently inhibits pancreatic tumor growth |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5190097/ https://www.ncbi.nlm.nih.gov/pubmed/27322423 http://dx.doi.org/10.18632/oncotarget.9996 |
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