Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth
Hirotaka Kanzaki,1 Avradip Chatterjee,1 Hanieh Hossein Nejad Ariani,1 Xinfeng Zhang,2 Stacey Chung,2 Nan Deng,3,4 V Krishnan Ramanujan,4 Xiaojiang Cui,1,2,4 Mark I Greene,5 Ramachandran Murali1 1Department of Biomedical Sciences, Research Division of Immunology; 2Department of Surgery; 3Biostatistic...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Dove Medical Press
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/2cec3693aa474d2fa8484fa9b96c5ce4 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:2cec3693aa474d2fa8484fa9b96c5ce4 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:2cec3693aa474d2fa8484fa9b96c5ce42021-12-02T15:24:22ZDisabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth1179-1314https://doaj.org/article/2cec3693aa474d2fa8484fa9b96c5ce42021-07-01T00:00:00Zhttps://www.dovepress.com/disabling-the-nuclear-translocalization-of-relanf-b-by-a-small-molecul-peer-reviewed-fulltext-article-BCTThttps://doaj.org/toc/1179-1314Hirotaka Kanzaki,1 Avradip Chatterjee,1 Hanieh Hossein Nejad Ariani,1 Xinfeng Zhang,2 Stacey Chung,2 Nan Deng,3,4 V Krishnan Ramanujan,4 Xiaojiang Cui,1,2,4 Mark I Greene,5 Ramachandran Murali1 1Department of Biomedical Sciences, Research Division of Immunology; 2Department of Surgery; 3Biostatistics and Bioinformatics Research Center; 4Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; 5Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USACorrespondence: Ramachandran Murali Email ramachandran.murali@csmc.eduIntroduction: Constitutive activation of NF-κB has been implicated as being contributive to cancer cell growth, drug resistance, and tumor recurrence in many cancers including breast cancer. Activation of NF-κB leads to nuclear translocation of RelA, a critical component of the NF-κB transcription factor complex, which subsequently binds to specific DNA sites and activates a multitude of genes involved in diverse cell functions. Studies show that triple-negative breast cancer (TNBC) cells possess constitutively active NF-κB and concomitantly have higher levels of nuclear localization of RelA than cytoplasmic RelA. This feature is considered to be associated with the response to chemotherapy. However, currently, there is no specific inhibitor to block nuclear translocation of RelA.Methods: A structure-based approach was used to develop a small-molecule inhibitor of RelA nuclear translocation. The interaction between this molecule and RelA was verified biophysically through isothermal titration calorimetry and microscale thermophoresis. TNBC cell lines MDA-MB-231 and MDA-MB-468 and a human TNBC xenograft model were used to verify in vitro and in vivo efficacy of the small molecule, respectively.Results: We found that the small molecule, CRL1101, bound specifically to RelA as indicated by the biophysical assays. Further, CRL1101 blocked RelA nuclear translocation in breast cancer cells in vitro, and markedly reduced breast tumor growth in a triple-negative breast cancer xenograft model.Conclusion: Our study demonstrates that CRL1101 may lead to new NF-κB-targeted therapeutics for TNBC. Further, blocking of nuclear translocation of shuttling transcription factors may be a useful general strategy in cancer drug development.Keywords: transcription factors, breast cancer, computer aided drug design, nuclear transport, drug-targetKanzaki HChatterjee AHossein Nejad Ariani HZhang XChung SDeng NRamanujan VKCui XGreene MIMurali RDove Medical Pressarticletranscription factorsbreast cancercomputer aided drug designnuclear transportdrug-targetNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 13, Pp 419-430 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
transcription factors breast cancer computer aided drug design nuclear transport drug-target Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
transcription factors breast cancer computer aided drug design nuclear transport drug-target Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Kanzaki H Chatterjee A Hossein Nejad Ariani H Zhang X Chung S Deng N Ramanujan VK Cui X Greene MI Murali R Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth |
| description |
Hirotaka Kanzaki,1 Avradip Chatterjee,1 Hanieh Hossein Nejad Ariani,1 Xinfeng Zhang,2 Stacey Chung,2 Nan Deng,3,4 V Krishnan Ramanujan,4 Xiaojiang Cui,1,2,4 Mark I Greene,5 Ramachandran Murali1 1Department of Biomedical Sciences, Research Division of Immunology; 2Department of Surgery; 3Biostatistics and Bioinformatics Research Center; 4Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; 5Department of Pathology and Laboratory of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USACorrespondence: Ramachandran Murali Email ramachandran.murali@csmc.eduIntroduction: Constitutive activation of NF-κB has been implicated as being contributive to cancer cell growth, drug resistance, and tumor recurrence in many cancers including breast cancer. Activation of NF-κB leads to nuclear translocation of RelA, a critical component of the NF-κB transcription factor complex, which subsequently binds to specific DNA sites and activates a multitude of genes involved in diverse cell functions. Studies show that triple-negative breast cancer (TNBC) cells possess constitutively active NF-κB and concomitantly have higher levels of nuclear localization of RelA than cytoplasmic RelA. This feature is considered to be associated with the response to chemotherapy. However, currently, there is no specific inhibitor to block nuclear translocation of RelA.Methods: A structure-based approach was used to develop a small-molecule inhibitor of RelA nuclear translocation. The interaction between this molecule and RelA was verified biophysically through isothermal titration calorimetry and microscale thermophoresis. TNBC cell lines MDA-MB-231 and MDA-MB-468 and a human TNBC xenograft model were used to verify in vitro and in vivo efficacy of the small molecule, respectively.Results: We found that the small molecule, CRL1101, bound specifically to RelA as indicated by the biophysical assays. Further, CRL1101 blocked RelA nuclear translocation in breast cancer cells in vitro, and markedly reduced breast tumor growth in a triple-negative breast cancer xenograft model.Conclusion: Our study demonstrates that CRL1101 may lead to new NF-κB-targeted therapeutics for TNBC. Further, blocking of nuclear translocation of shuttling transcription factors may be a useful general strategy in cancer drug development.Keywords: transcription factors, breast cancer, computer aided drug design, nuclear transport, drug-target |
| format |
article |
| author |
Kanzaki H Chatterjee A Hossein Nejad Ariani H Zhang X Chung S Deng N Ramanujan VK Cui X Greene MI Murali R |
| author_facet |
Kanzaki H Chatterjee A Hossein Nejad Ariani H Zhang X Chung S Deng N Ramanujan VK Cui X Greene MI Murali R |
| author_sort |
Kanzaki H |
| title |
Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth |
| title_short |
Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth |
| title_full |
Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth |
| title_fullStr |
Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth |
| title_full_unstemmed |
Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer Growth |
| title_sort |
disabling the nuclear translocalization of rela/nf-κb by a small molecule inhibits triple-negative breast cancer growth |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/2cec3693aa474d2fa8484fa9b96c5ce4 |
| work_keys_str_mv |
AT kanzakih disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT chatterjeea disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT hosseinnejadarianih disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT zhangx disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT chungs disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT dengn disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT ramanujanvk disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT cuix disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT greenemi disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth AT muralir disablingthenucleartranslocalizationofrelanfkappabbyasmallmoleculeinhibitstriplenegativebreastcancergrowth |
| _version_ |
1718387252865794048 |