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NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling
Aberrant activation of the cholesterol biosynthesis supports tumor cell growth. In recent years, significant progress has been made by targeting rate-limiting enzymes in cholesterol biosynthesis pathways to prevent carcinogenesis. However, precise mechanisms behind cholesterol degradation in cancer...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425431/ https://www.ncbi.nlm.nih.gov/pubmed/32712598 http://dx.doi.org/10.18632/aging.103562 |
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author | Liu, Jia Cao, Lei Qu, Jun-Ze Chen, Ting-Ting Su, Zi-Jie Hu, Yun-Long Wang, Ying Yao, Ming-Dong Xiao, Wen-Hai Li, Chun Li, Bo Yuan, Ying-Jin |
author_facet | Liu, Jia Cao, Lei Qu, Jun-Ze Chen, Ting-Ting Su, Zi-Jie Hu, Yun-Long Wang, Ying Yao, Ming-Dong Xiao, Wen-Hai Li, Chun Li, Bo Yuan, Ying-Jin |
author_sort | Liu, Jia |
collection | PubMed |
description | Aberrant activation of the cholesterol biosynthesis supports tumor cell growth. In recent years, significant progress has been made by targeting rate-limiting enzymes in cholesterol biosynthesis pathways to prevent carcinogenesis. However, precise mechanisms behind cholesterol degradation in cancer cells have not been comprehensively investigated. Here, we report that codon optimization of the orthologous cholesterol 7-desaturase, NVD-BM from Bombyx mori, significantly slowed melanoma cell proliferation and migration, and inhibited cancer cell engraftment in nude mice, by converting cholesterol to toxic 7-dehydrocholesterol. Based on these observations, we established a synthetic genetic circuit to induce melanoma cell regression by sensing tumor specific signals in melanoma cells. The dual-input signals, RELA proto-oncogene (RELA) and signal transducer and activator of transcription 1 (STAT1), activated NVD-BM expression and repressed melanoma cell proliferation and migration. Mechanically, we observed that NVD-BM decreased Akt1-ser473 phosphorylation and inhibited cytoplasmic RELA translocation. Taken together, NVD-BM was identified as a tumor suppressor in malignant melanoma, and we established a dual-input biosensor to promote cancer cell regression, via Akt1/NF-κB signaling. Our results demonstrate the potential therapeutic effects of cholesterol 7-desaturase in melanoma metabolism, and provides insights for genetic circuits targeting 7-dehydrocholesterol accumulation in tumors. |
format | Online Article Text |
id | pubmed-7425431 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-74254312020-08-25 NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling Liu, Jia Cao, Lei Qu, Jun-Ze Chen, Ting-Ting Su, Zi-Jie Hu, Yun-Long Wang, Ying Yao, Ming-Dong Xiao, Wen-Hai Li, Chun Li, Bo Yuan, Ying-Jin Aging (Albany NY) Research Paper Aberrant activation of the cholesterol biosynthesis supports tumor cell growth. In recent years, significant progress has been made by targeting rate-limiting enzymes in cholesterol biosynthesis pathways to prevent carcinogenesis. However, precise mechanisms behind cholesterol degradation in cancer cells have not been comprehensively investigated. Here, we report that codon optimization of the orthologous cholesterol 7-desaturase, NVD-BM from Bombyx mori, significantly slowed melanoma cell proliferation and migration, and inhibited cancer cell engraftment in nude mice, by converting cholesterol to toxic 7-dehydrocholesterol. Based on these observations, we established a synthetic genetic circuit to induce melanoma cell regression by sensing tumor specific signals in melanoma cells. The dual-input signals, RELA proto-oncogene (RELA) and signal transducer and activator of transcription 1 (STAT1), activated NVD-BM expression and repressed melanoma cell proliferation and migration. Mechanically, we observed that NVD-BM decreased Akt1-ser473 phosphorylation and inhibited cytoplasmic RELA translocation. Taken together, NVD-BM was identified as a tumor suppressor in malignant melanoma, and we established a dual-input biosensor to promote cancer cell regression, via Akt1/NF-κB signaling. Our results demonstrate the potential therapeutic effects of cholesterol 7-desaturase in melanoma metabolism, and provides insights for genetic circuits targeting 7-dehydrocholesterol accumulation in tumors. Impact Journals 2020-07-25 /pmc/articles/PMC7425431/ /pubmed/32712598 http://dx.doi.org/10.18632/aging.103562 Text en Copyright © 2020 Liu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Liu, Jia Cao, Lei Qu, Jun-Ze Chen, Ting-Ting Su, Zi-Jie Hu, Yun-Long Wang, Ying Yao, Ming-Dong Xiao, Wen-Hai Li, Chun Li, Bo Yuan, Ying-Jin NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling |
title | NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling |
title_full | NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling |
title_fullStr | NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling |
title_full_unstemmed | NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling |
title_short | NVD-BM-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via Akt1/NF-ĸB signaling |
title_sort | nvd-bm-mediated genetic biosensor triggers accumulation of 7-dehydrocholesterol and inhibits melanoma via akt1/nf-ĸb signaling |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425431/ https://www.ncbi.nlm.nih.gov/pubmed/32712598 http://dx.doi.org/10.18632/aging.103562 |
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