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Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation

The WASF3 gene promotes cancer cell invasion and metastasis, and genetic inactivation leads to suppression of metastasis. To identify small molecules that might interfere with WASF3 function, we performed an in silico docking study to the regulatory pocket of WASF3 using the National Cancer Institut...

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Autores principales: Silva, Jeane, Omar, Nivin, Sittaramane, Vinoth, Cowell, John K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10585217/
https://www.ncbi.nlm.nih.gov/pubmed/37867831
http://dx.doi.org/10.1016/j.heliyon.2023.e20662
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author Silva, Jeane
Omar, Nivin
Sittaramane, Vinoth
Cowell, John K.
author_facet Silva, Jeane
Omar, Nivin
Sittaramane, Vinoth
Cowell, John K.
author_sort Silva, Jeane
collection PubMed
description The WASF3 gene promotes cancer cell invasion and metastasis, and genetic inactivation leads to suppression of metastasis. To identify small molecules that might interfere with WASF3 function, we performed an in silico docking study to the regulatory pocket of WASF3 using the National Cancer Institute (NCI) diversity set VI small molecule library. Compounds that showed the maximum likelihood of interaction with WASF3 were screened for their effect on cell movement in breast and prostate cancer cells, a well-established predictor of invasion and metastasis. Three hit compounds were identified that affected cell movement, and the same compounds also suppressed cell migration and invasion in vitro in both MDA-MB-231 breast cancer cells and Du145 prostate cancer cells. Using a zebrafish metastasis assay, one of these compounds, NSC670283, showed significant suppression of metastasis in vivo while not affecting cell proliferation. NSC670283 showed a consistent effect on suppression of invasion and metastasis, and cellular temperature shift assays provided support for physical interaction with WASF3. In addition, suppression of cell movement and invasion was accompanied by a decrease in actin filament polymerization. The data in this study suggest that these small molecules inhibit cancer cell invasion and metastasis, and to our knowledge, it is the first identification of a small molecule that can potentially inhibit WASF3-directed metastasis, laying the foundation for medicinal chemistry approaches to enhance the potency of the identified compounds.
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spelling pubmed-105852172023-10-20 Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation Silva, Jeane Omar, Nivin Sittaramane, Vinoth Cowell, John K. Heliyon Research Article The WASF3 gene promotes cancer cell invasion and metastasis, and genetic inactivation leads to suppression of metastasis. To identify small molecules that might interfere with WASF3 function, we performed an in silico docking study to the regulatory pocket of WASF3 using the National Cancer Institute (NCI) diversity set VI small molecule library. Compounds that showed the maximum likelihood of interaction with WASF3 were screened for their effect on cell movement in breast and prostate cancer cells, a well-established predictor of invasion and metastasis. Three hit compounds were identified that affected cell movement, and the same compounds also suppressed cell migration and invasion in vitro in both MDA-MB-231 breast cancer cells and Du145 prostate cancer cells. Using a zebrafish metastasis assay, one of these compounds, NSC670283, showed significant suppression of metastasis in vivo while not affecting cell proliferation. NSC670283 showed a consistent effect on suppression of invasion and metastasis, and cellular temperature shift assays provided support for physical interaction with WASF3. In addition, suppression of cell movement and invasion was accompanied by a decrease in actin filament polymerization. The data in this study suggest that these small molecules inhibit cancer cell invasion and metastasis, and to our knowledge, it is the first identification of a small molecule that can potentially inhibit WASF3-directed metastasis, laying the foundation for medicinal chemistry approaches to enhance the potency of the identified compounds. Elsevier 2023-10-10 /pmc/articles/PMC10585217/ /pubmed/37867831 http://dx.doi.org/10.1016/j.heliyon.2023.e20662 Text en Published by Elsevier Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Silva, Jeane
Omar, Nivin
Sittaramane, Vinoth
Cowell, John K.
Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation
title Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation
title_full Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation
title_fullStr Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation
title_full_unstemmed Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation
title_short Identification of small molecules that suppress cell invasion and metastasis promoted by WASF3 activation
title_sort identification of small molecules that suppress cell invasion and metastasis promoted by wasf3 activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10585217/
https://www.ncbi.nlm.nih.gov/pubmed/37867831
http://dx.doi.org/10.1016/j.heliyon.2023.e20662
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