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Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells

The enlarged distinct bulky-ball-like nucleolus matrix assembly is observed in most cancer stem cells (CSCs); however, the underlying mechanism is largely unknown. We show that matrix metalloproteinase-7 (MMP-7) shedding MUC-1 SEA domain releases MUC-1 C-ter, facilitating the nucleolus trafficking o...

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Autores principales: Yu, Wei-Hsuan, Wu, Erxi, Li, Yongqing, Hou, Hsin-Han, Yu, Shuan-su C., Huang, Po-Tsang, Kuo, Wen-Hung, Qi, Dan, Yu, Chong-Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559243/
https://www.ncbi.nlm.nih.gov/pubmed/33089100
http://dx.doi.org/10.1016/j.isci.2020.101600
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author Yu, Wei-Hsuan
Wu, Erxi
Li, Yongqing
Hou, Hsin-Han
Yu, Shuan-su C.
Huang, Po-Tsang
Kuo, Wen-Hung
Qi, Dan
Yu, Chong-Jen
author_facet Yu, Wei-Hsuan
Wu, Erxi
Li, Yongqing
Hou, Hsin-Han
Yu, Shuan-su C.
Huang, Po-Tsang
Kuo, Wen-Hung
Qi, Dan
Yu, Chong-Jen
author_sort Yu, Wei-Hsuan
collection PubMed
description The enlarged distinct bulky-ball-like nucleolus matrix assembly is observed in most cancer stem cells (CSCs); however, the underlying mechanism is largely unknown. We show that matrix metalloproteinase-7 (MMP-7) shedding MUC-1 SEA domain releases MUC-1 C-ter, facilitating the nucleolus trafficking of p53 in gefitinib-resistant lung CSCs. The nucleolus colocalizations of p53, MUC-1 C-ter, MMP-7 and nucleolin were observed in the CD34(+) CXADR(+) CD44v(3)(+) gefitinib-resistant EGFR(L858R/T790M) CSC colonies. MUC-1 C-ter induced a unique porous bulky-ball-shaped, cagelike nucleolus that functions as a nucleus molecular “garage” for potent tumor suppressor, p53. Nucleolus could also facilitate the novel sub-nucleus compartment for proteolytic processing p53 by MMP-7 to generate a 35 kDa fragment. Moreover, we show that salinomycin, an anti-CSC agent, disrupts nucleolus by inducing nucleoplasm translocation of p53 and sensitizing CSC to chemotherapy drugs. Thus, this study highlights the MMP-7-MUC-1-p53 axis in nucleolus as a potential therapeutic target for anti-CSCs to resolve the chemotherapy-resistance dilemma.
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spelling pubmed-75592432020-10-20 Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells Yu, Wei-Hsuan Wu, Erxi Li, Yongqing Hou, Hsin-Han Yu, Shuan-su C. Huang, Po-Tsang Kuo, Wen-Hung Qi, Dan Yu, Chong-Jen iScience Article The enlarged distinct bulky-ball-like nucleolus matrix assembly is observed in most cancer stem cells (CSCs); however, the underlying mechanism is largely unknown. We show that matrix metalloproteinase-7 (MMP-7) shedding MUC-1 SEA domain releases MUC-1 C-ter, facilitating the nucleolus trafficking of p53 in gefitinib-resistant lung CSCs. The nucleolus colocalizations of p53, MUC-1 C-ter, MMP-7 and nucleolin were observed in the CD34(+) CXADR(+) CD44v(3)(+) gefitinib-resistant EGFR(L858R/T790M) CSC colonies. MUC-1 C-ter induced a unique porous bulky-ball-shaped, cagelike nucleolus that functions as a nucleus molecular “garage” for potent tumor suppressor, p53. Nucleolus could also facilitate the novel sub-nucleus compartment for proteolytic processing p53 by MMP-7 to generate a 35 kDa fragment. Moreover, we show that salinomycin, an anti-CSC agent, disrupts nucleolus by inducing nucleoplasm translocation of p53 and sensitizing CSC to chemotherapy drugs. Thus, this study highlights the MMP-7-MUC-1-p53 axis in nucleolus as a potential therapeutic target for anti-CSCs to resolve the chemotherapy-resistance dilemma. Elsevier 2020-09-23 /pmc/articles/PMC7559243/ /pubmed/33089100 http://dx.doi.org/10.1016/j.isci.2020.101600 Text en © 2020 The Authors http://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 Article
Yu, Wei-Hsuan
Wu, Erxi
Li, Yongqing
Hou, Hsin-Han
Yu, Shuan-su C.
Huang, Po-Tsang
Kuo, Wen-Hung
Qi, Dan
Yu, Chong-Jen
Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells
title Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells
title_full Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells
title_fullStr Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells
title_full_unstemmed Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells
title_short Matrix Metalloprotease-7 Mediates Nucleolar Assembly and Intra-nucleolar Cleaving p53 in Gefitinib-Resistant Cancer Stem Cells
title_sort matrix metalloprotease-7 mediates nucleolar assembly and intra-nucleolar cleaving p53 in gefitinib-resistant cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559243/
https://www.ncbi.nlm.nih.gov/pubmed/33089100
http://dx.doi.org/10.1016/j.isci.2020.101600
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