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A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer

Cancers remain a threat to human health due to the lack of effective therapeutic strategies. Great effort has been devoted to the discovery of drug targets to treat cancers, but novel oncoproteins still need to be unveiled for efficient therapy. Methods: We show that CREPT is highly expressed in pan...

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Autores principales: Ma, Danhui, Zou, Yutian, Chu, Yunxiang, Liu, Zhengsheng, Liu, Gaochao, Chu, Jun, Li, Mengdi, Wang, Jiayu, Sun, Shi-yong, Chang, Zhijie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069095/
https://www.ncbi.nlm.nih.gov/pubmed/32206117
http://dx.doi.org/10.7150/thno.41677
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author Ma, Danhui
Zou, Yutian
Chu, Yunxiang
Liu, Zhengsheng
Liu, Gaochao
Chu, Jun
Li, Mengdi
Wang, Jiayu
Sun, Shi-yong
Chang, Zhijie
author_facet Ma, Danhui
Zou, Yutian
Chu, Yunxiang
Liu, Zhengsheng
Liu, Gaochao
Chu, Jun
Li, Mengdi
Wang, Jiayu
Sun, Shi-yong
Chang, Zhijie
author_sort Ma, Danhui
collection PubMed
description Cancers remain a threat to human health due to the lack of effective therapeutic strategies. Great effort has been devoted to the discovery of drug targets to treat cancers, but novel oncoproteins still need to be unveiled for efficient therapy. Methods: We show that CREPT is highly expressed in pancreatic cancer and is associated with poor disease-free survival. CREPT overexpression promotes but CREPT deletion blocks colony formation and proliferation of pancreatic cancer cells. To provide a proof of concept for CREPT as a new target for the inhibition of pancreatic cancer, we designed a cell-permeable peptide-based proteolysis targeting chimera (PROTAC), named PRTC, based on the homodimerized leucine-zipper-like motif in the C-terminus domain of CREPT to induce its degradation in vivo. Results: PRTC has high affinity for CREPT, with Kd = 0.34 +/- 0.11 μM and is able to permeate into cells because of the attached membrane-transportable peptide RRRRK. PRTC effectively induces CREPT degradation in a proteasome-dependent manner. Intriguingly, PRTC inhibits colony formation, cell proliferation, and motility in pancreatic cancer cells and ultimately impairs xenograft tumor growth, comparable to the effect of CREPT deletion. Conclusions: PRTC-induced degradation of CREPT leads to inhibition of tumor growth, which is promising for the development of new drugs against pancreatic cancer. In addition, using an interacting motif based on the dimerized structure of proteins may be a new way to design a PROTAC aiming at degrading any protein without known interacting small molecules or peptides.
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spelling pubmed-70690952020-03-23 A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer Ma, Danhui Zou, Yutian Chu, Yunxiang Liu, Zhengsheng Liu, Gaochao Chu, Jun Li, Mengdi Wang, Jiayu Sun, Shi-yong Chang, Zhijie Theranostics Research Paper Cancers remain a threat to human health due to the lack of effective therapeutic strategies. Great effort has been devoted to the discovery of drug targets to treat cancers, but novel oncoproteins still need to be unveiled for efficient therapy. Methods: We show that CREPT is highly expressed in pancreatic cancer and is associated with poor disease-free survival. CREPT overexpression promotes but CREPT deletion blocks colony formation and proliferation of pancreatic cancer cells. To provide a proof of concept for CREPT as a new target for the inhibition of pancreatic cancer, we designed a cell-permeable peptide-based proteolysis targeting chimera (PROTAC), named PRTC, based on the homodimerized leucine-zipper-like motif in the C-terminus domain of CREPT to induce its degradation in vivo. Results: PRTC has high affinity for CREPT, with Kd = 0.34 +/- 0.11 μM and is able to permeate into cells because of the attached membrane-transportable peptide RRRRK. PRTC effectively induces CREPT degradation in a proteasome-dependent manner. Intriguingly, PRTC inhibits colony formation, cell proliferation, and motility in pancreatic cancer cells and ultimately impairs xenograft tumor growth, comparable to the effect of CREPT deletion. Conclusions: PRTC-induced degradation of CREPT leads to inhibition of tumor growth, which is promising for the development of new drugs against pancreatic cancer. In addition, using an interacting motif based on the dimerized structure of proteins may be a new way to design a PROTAC aiming at degrading any protein without known interacting small molecules or peptides. Ivyspring International Publisher 2020-02-19 /pmc/articles/PMC7069095/ /pubmed/32206117 http://dx.doi.org/10.7150/thno.41677 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Ma, Danhui
Zou, Yutian
Chu, Yunxiang
Liu, Zhengsheng
Liu, Gaochao
Chu, Jun
Li, Mengdi
Wang, Jiayu
Sun, Shi-yong
Chang, Zhijie
A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
title A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
title_full A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
title_fullStr A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
title_full_unstemmed A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
title_short A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer
title_sort cell-permeable peptide-based protac against the oncoprotein crept proficiently inhibits pancreatic cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069095/
https://www.ncbi.nlm.nih.gov/pubmed/32206117
http://dx.doi.org/10.7150/thno.41677
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