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A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells

p53, the major tumor suppressor, is frequently mutated in many cancers, and up to 84% of human melanomas harbor wild-type p53, which is considered to be an ideal target for melanoma therapy. Here, we evaluated the antitumor activity of a carbazole derivative, 9-ethyl-9H-carbazole-3-carbaldehyde (ECC...

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Autores principales: Wen, Jie, Chen, Wenqian, Zhao, Baoxiang, Xu, Qiuping, Liu, Chang, Zhang, Qun, Xie, Zhiwei, Yan, Yonggan, Guo, Jing, Huang, Jun, Miao, Junying, Wu, Xunwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187445/
https://www.ncbi.nlm.nih.gov/pubmed/34103468
http://dx.doi.org/10.1038/s41419-021-03867-6
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author Wen, Jie
Chen, Wenqian
Zhao, Baoxiang
Xu, Qiuping
Liu, Chang
Zhang, Qun
Xie, Zhiwei
Yan, Yonggan
Guo, Jing
Huang, Jun
Miao, Junying
Wu, Xunwei
author_facet Wen, Jie
Chen, Wenqian
Zhao, Baoxiang
Xu, Qiuping
Liu, Chang
Zhang, Qun
Xie, Zhiwei
Yan, Yonggan
Guo, Jing
Huang, Jun
Miao, Junying
Wu, Xunwei
author_sort Wen, Jie
collection PubMed
description p53, the major tumor suppressor, is frequently mutated in many cancers, and up to 84% of human melanomas harbor wild-type p53, which is considered to be an ideal target for melanoma therapy. Here, we evaluated the antitumor activity of a carbazole derivative, 9-ethyl-9H-carbazole-3-carbaldehyde (ECCA), on melanoma cells. ECCA had a selectively strong inhibitory activity against the growth of BRAF-mutated and BRAF-wild-type melanoma cells but had little effect on normal human primary melanocytes. ECCA inhibited melanoma cell growth by increasing cell apoptosis, which was associated with the upregulation of caspase activities and was significantly abrogated by the addition of a caspase inhibitor. In vivo assays confirmed that ECCA suppressed melanoma growth by enhancing cell apoptosis and reducing cell proliferation, and importantly ECCA did not have any evident toxic effects on normal tissues. RNA-Seq analysis identified several pathways related to cell apoptosis that were affected by ECCA, notably, activation of the p53 signaling pathway. Biochemical assays demonstrated that ECCA enhanced the phosphorylation of p53 at Ser15 in melanoma cells harboring wild-type p53, and importantly, the knockdown or deletion of p53 in those cells counteracted the ECCA-induced apoptosis, as well as senescence. Further investigations revealed that ECCA enhanced the phosphorylation of p38-MAPK and c-Jun N-terminal kinase (JNK), and treatment with either a p38-MAPK or a JNK inhibitor rescued the cell growth inhibition elicited by ECCA, which depended on the expression of the p53 gene. Finally, the combination of ECCA with a BRAF inhibitor significantly enhanced the growth inhibition of melanoma cells. In summary, our study demonstrates that the carbazole derivative, ECCA, induces melanoma cell apoptosis and senescence through the activation of p53 to significantly and selectively suppress the growth of melanoma cells without affecting normal human melanocytes, suggesting its potential to develop a new drug for melanoma therapy.
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spelling pubmed-81874452021-06-28 A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells Wen, Jie Chen, Wenqian Zhao, Baoxiang Xu, Qiuping Liu, Chang Zhang, Qun Xie, Zhiwei Yan, Yonggan Guo, Jing Huang, Jun Miao, Junying Wu, Xunwei Cell Death Dis Article p53, the major tumor suppressor, is frequently mutated in many cancers, and up to 84% of human melanomas harbor wild-type p53, which is considered to be an ideal target for melanoma therapy. Here, we evaluated the antitumor activity of a carbazole derivative, 9-ethyl-9H-carbazole-3-carbaldehyde (ECCA), on melanoma cells. ECCA had a selectively strong inhibitory activity against the growth of BRAF-mutated and BRAF-wild-type melanoma cells but had little effect on normal human primary melanocytes. ECCA inhibited melanoma cell growth by increasing cell apoptosis, which was associated with the upregulation of caspase activities and was significantly abrogated by the addition of a caspase inhibitor. In vivo assays confirmed that ECCA suppressed melanoma growth by enhancing cell apoptosis and reducing cell proliferation, and importantly ECCA did not have any evident toxic effects on normal tissues. RNA-Seq analysis identified several pathways related to cell apoptosis that were affected by ECCA, notably, activation of the p53 signaling pathway. Biochemical assays demonstrated that ECCA enhanced the phosphorylation of p53 at Ser15 in melanoma cells harboring wild-type p53, and importantly, the knockdown or deletion of p53 in those cells counteracted the ECCA-induced apoptosis, as well as senescence. Further investigations revealed that ECCA enhanced the phosphorylation of p38-MAPK and c-Jun N-terminal kinase (JNK), and treatment with either a p38-MAPK or a JNK inhibitor rescued the cell growth inhibition elicited by ECCA, which depended on the expression of the p53 gene. Finally, the combination of ECCA with a BRAF inhibitor significantly enhanced the growth inhibition of melanoma cells. In summary, our study demonstrates that the carbazole derivative, ECCA, induces melanoma cell apoptosis and senescence through the activation of p53 to significantly and selectively suppress the growth of melanoma cells without affecting normal human melanocytes, suggesting its potential to develop a new drug for melanoma therapy. Nature Publishing Group UK 2021-06-08 /pmc/articles/PMC8187445/ /pubmed/34103468 http://dx.doi.org/10.1038/s41419-021-03867-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wen, Jie
Chen, Wenqian
Zhao, Baoxiang
Xu, Qiuping
Liu, Chang
Zhang, Qun
Xie, Zhiwei
Yan, Yonggan
Guo, Jing
Huang, Jun
Miao, Junying
Wu, Xunwei
A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
title A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
title_full A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
title_fullStr A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
title_full_unstemmed A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
title_short A carbazole compound, 9-ethyl-9H-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
title_sort carbazole compound, 9-ethyl-9h-carbazole-3-carbaldehyde, plays an antitumor function through reactivation of the p53 pathway in human melanoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187445/
https://www.ncbi.nlm.nih.gov/pubmed/34103468
http://dx.doi.org/10.1038/s41419-021-03867-6
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