Cargando…
Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer
While targeted agents are an important part of the treatment arsenal for colorectal cancer, there is still a lack of efficient small-molecule targeted agents based on the understanding of pathogenic molecular mechanisms. In this study, curcumin analog RL71 displayed potent cytotoxicity towards human...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741952/ https://www.ncbi.nlm.nih.gov/pubmed/26608678 |
_version_ | 1782414107609137152 |
---|---|
author | Yang, Baofang Zhang, Minxia Gao, Jian Li, Jiahuang Fan, Lu Xiang, Gang Wang, Xingqi Wang, Xiaoning Wu, Xuefeng Sun, Yang Wu, Xudong Liang, Guang Shen, Yan Xu, Qiang |
author_facet | Yang, Baofang Zhang, Minxia Gao, Jian Li, Jiahuang Fan, Lu Xiang, Gang Wang, Xingqi Wang, Xiaoning Wu, Xuefeng Sun, Yang Wu, Xudong Liang, Guang Shen, Yan Xu, Qiang |
author_sort | Yang, Baofang |
collection | PubMed |
description | While targeted agents are an important part of the treatment arsenal for colorectal cancer, there is still a lack of efficient small-molecule targeted agents based on the understanding of pathogenic molecular mechanisms. In this study, curcumin analog RL71 displayed potent cytotoxicity towards human colon cancer cells with an IC(50) of 0.8 μM in SW480 cells and inhibited xenotransplanted tumor growth in a dose-dependent manner. Using affinity chromatography, we identified sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2 as the binding target of RL71. Most notably, RL71 demonstrated special binding to SERCA2 at a novel site with the lowest estimated free energy −8.89 kcal mol(−1), and the SERCA2 residues critical for RL71 binding were identified. RL71 suppressed the Ca(2+)-ATPase activity of SERCA2 both in vitro and in vivo, accompanied by the induction of endoplasmic reticulum stress leading to apoptosis and G2/M cycle arrest in SW480 cells. In addition, RL71 showed synergistic cytotoxicity with the pan-SERCA inhibitor thapsigargin. These results suggest that RL71 could be a selective small-molecule inhibitor of SERCA2, and that it may serve as a lead compound for the study of targeted colorectal cancer therapy. |
format | Online Article Text |
id | pubmed-4741952 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-47419522016-03-17 Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer Yang, Baofang Zhang, Minxia Gao, Jian Li, Jiahuang Fan, Lu Xiang, Gang Wang, Xingqi Wang, Xiaoning Wu, Xuefeng Sun, Yang Wu, Xudong Liang, Guang Shen, Yan Xu, Qiang Oncotarget Research Paper While targeted agents are an important part of the treatment arsenal for colorectal cancer, there is still a lack of efficient small-molecule targeted agents based on the understanding of pathogenic molecular mechanisms. In this study, curcumin analog RL71 displayed potent cytotoxicity towards human colon cancer cells with an IC(50) of 0.8 μM in SW480 cells and inhibited xenotransplanted tumor growth in a dose-dependent manner. Using affinity chromatography, we identified sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2 as the binding target of RL71. Most notably, RL71 demonstrated special binding to SERCA2 at a novel site with the lowest estimated free energy −8.89 kcal mol(−1), and the SERCA2 residues critical for RL71 binding were identified. RL71 suppressed the Ca(2+)-ATPase activity of SERCA2 both in vitro and in vivo, accompanied by the induction of endoplasmic reticulum stress leading to apoptosis and G2/M cycle arrest in SW480 cells. In addition, RL71 showed synergistic cytotoxicity with the pan-SERCA inhibitor thapsigargin. These results suggest that RL71 could be a selective small-molecule inhibitor of SERCA2, and that it may serve as a lead compound for the study of targeted colorectal cancer therapy. Impact Journals LLC 2015-10-10 /pmc/articles/PMC4741952/ /pubmed/26608678 Text en Copyright: © 2015 Yang 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 Yang, Baofang Zhang, Minxia Gao, Jian Li, Jiahuang Fan, Lu Xiang, Gang Wang, Xingqi Wang, Xiaoning Wu, Xuefeng Sun, Yang Wu, Xudong Liang, Guang Shen, Yan Xu, Qiang Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer |
title | Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer |
title_full | Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer |
title_fullStr | Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer |
title_full_unstemmed | Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer |
title_short | Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer |
title_sort | small molecule rl71 targets serca2 at a novel site in the treatment of human colorectal cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741952/ https://www.ncbi.nlm.nih.gov/pubmed/26608678 |
work_keys_str_mv | AT yangbaofang smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT zhangminxia smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT gaojian smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT lijiahuang smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT fanlu smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT xianggang smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT wangxingqi smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT wangxiaoning smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT wuxuefeng smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT sunyang smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT wuxudong smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT liangguang smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT shenyan smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer AT xuqiang smallmoleculerl71targetsserca2atanovelsiteinthetreatmentofhumancolorectalcancer |