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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...

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Autores principales: Pan, Ting, Zhang, Yiwen, Zhou, Nan, He, Xin, Chen, Cancan, Liang, Liting, Duan, Xiaobing, Lin, Yingtong, Wu, Kang, Zhang, Hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
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.
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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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