Small molecule activator of Nm23/NDPK as an inhibitor of metastasis
| Autor: | Ji Wan Suh, Hee-Yoon Lee, Jung Eun Choi, Hongsoo Lee, Sang Chul Shin, Ho-Young Lee, Eunice Eun Kyeong Kim, Eunsun Lee, Kong-Joo Lee, Dong Hae Shin, Ji Sun Lee, Eun Kyoung Seo, Hwang Suk Kim, Jae-Jin Lee, Jimin Park, Soonwha Song |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
rac1 GTP-Binding Protein
0301 basic medicine Cell Survival Allosteric regulation lcsh:Medicine Breast Neoplasms RAC1 Article Metastasis Small Molecule Libraries Mice Structure-Activity Relationship 03 medical and health sciences Allosteric Regulation Downregulation and upregulation Cell Movement Cell Line Tumor medicine Animals Humans Metastasis suppressor Neoplasm Metastasis lcsh:Science Cell Proliferation Multidisciplinary Activator (genetics) Chemistry Kinase lcsh:R NM23 Nucleoside Diphosphate Kinases medicine.disease Xenograft Model Antitumor Assays Nucleoside-diphosphate kinase Up-Regulation Gene Expression Regulation Neoplastic Treatment Outcome 030104 developmental biology Cancer research Female lcsh:Q |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-018-29101-6 |
| Popis: | Nm23-H1/NDPK-A is a tumor metastasis suppressor having NDP kinase (NDPK) activity. Nm23-H1 is positively associated with prolonged disease-free survival and good prognosis of cancer patients. Approaches to increasing the cellular levels of Nm23-H1 therefore have significance in the therapy of metastatic cancers. We found a small molecule, (±)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene, that activates Nm23, hereafter called NMac1. NMac1 directly binds to Nm23-H1 and increases its NDPK activity. Employing various NMac1 derivatives and hydrogen/deuterium mass spectrometry (HDX-MS), we identified the pharmacophore and mode of action of NMac1. We found that NMac1 binds to the C-terminal of Nm23-H1 and induces the NDPK activation through its allosteric conformational changes. NMac1-treated MDA-MB-231 breast cancer cells showed dramatic changes in morphology and actin-cytoskeletal organization following inhibition of Rac1 activation. NMac1 also suppressed invasion and migration in vitro, and metastasis in vivo, in a breast cancer mouse model. NMac1 as an activator of NDPK has potential as an anti-metastatic agent. |
| Databáze: | OpenAIRE |
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