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Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer
- Source :
- Oncotarget
- Publication Year :
- 2015
- Publisher :
- Impact Journals, LLC, 2015.
-
Abstract
- 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 IC50 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.
- Subjects :
- Curcumin
novel binding site
SERCA
Thapsigargin
Blotting, Western
Mice, Nude
Antineoplastic Agents
Apoptosis
colorectal cancer
Pharmacology
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Immunoenzyme Techniques
Mice
chemistry.chemical_compound
Diarylheptanoids
In vivo
Tumor Cells, Cultured
Animals
Humans
Medicine
Cytotoxicity
Cell Proliferation
targeted agent
Cell growth
business.industry
RL71
Endoplasmic reticulum
Cell Cycle
Cell cycle
Endoplasmic Reticulum Stress
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
SERCA2
Oncology
chemistry
Cancer research
Calcium
Female
Colorectal Neoplasms
business
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....3fa96b736fc4e6384f13b4ad4f7a142b