Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783505711157739520 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7069095 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT madanhui acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT zouyutian acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT chuyunxiang acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT liuzhengsheng acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT liugaochao acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT chujun acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT limengdi acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT wangjiayu acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT sunshiyong acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT changzhijie acellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT madanhui cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT zouyutian cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT chuyunxiang cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT liuzhengsheng cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT liugaochao cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT chujun cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT limengdi cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT wangjiayu cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT sunshiyong cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer AT changzhijie cellpermeablepeptidebasedprotacagainsttheoncoproteincreptproficientlyinhibitspancreaticcancer |