Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved..
BACKGROUND & AIMS: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression.
METHODS: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated in vitro, in vivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1+/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry.
RESULTS: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation in vitro. NEDDylation depletion (pevonedistat or Nae1+/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA in vivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells in vitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration.
CONCLUSION: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, NEDDylation impacts the CCA-stroma crosstalk. Inhibition of NEDDylation with pevonedistat may represent a potential therapeutic strategy for patients with CCA.
LAY SUMMARY: Little is known about the role of post-translational modifications of proteins in cholangiocarcinoma development and progression. Herein, we show that protein NEDDylation is upregulated and hyperactivated in cholangiocarcinoma, promoting tumor growth. Pharmacological inhibition of NEDDylation halts cholangiocarcinogenesis and could be an effective therapeutic strategy to tackle these tumors.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:77 |
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| Enthalten in: |
Journal of hepatology - 77(2022), 1 vom: 01. Juli, Seite 177-190 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Olaizola, Paula [VerfasserIn] |
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| Links: |
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| Themen: |
Cholangiocarcinoma |
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| Anmerkungen: |
Date Completed 21.06.2022 Date Revised 04.10.2022 published: Print-Electronic CommentIn: J Hepatol. 2022 Jul;77(1):12-14. - PMID 35490843 Citation Status MEDLINE |
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| doi: |
10.1016/j.jhep.2022.02.007 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM337485712 |
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| 100 | 1 | |a Olaizola, Paula |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Targeting NAE1-mediated protein hyper-NEDDylation halts cholangiocarcinogenesis and impacts on tumor-stroma crosstalk in experimental models |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 21.06.2022 | ||
| 500 | |a Date Revised 04.10.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: J Hepatol. 2022 Jul;77(1):12-14. - PMID 35490843 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a BACKGROUND & AIMS: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression | ||
| 520 | |a METHODS: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated in vitro, in vivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1+/- mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry | ||
| 520 | |a RESULTS: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation in vitro. NEDDylation depletion (pevonedistat or Nae1+/- mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogene-driven models of CCA in vivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells in vitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration | ||
| 520 | |a CONCLUSION: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, NEDDylation impacts the CCA-stroma crosstalk. Inhibition of NEDDylation with pevonedistat may represent a potential therapeutic strategy for patients with CCA | ||
| 520 | |a LAY SUMMARY: Little is known about the role of post-translational modifications of proteins in cholangiocarcinoma development and progression. Herein, we show that protein NEDDylation is upregulated and hyperactivated in cholangiocarcinoma, promoting tumor growth. Pharmacological inhibition of NEDDylation halts cholangiocarcinogenesis and could be an effective therapeutic strategy to tackle these tumors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cholangiocarcinoma | |
| 650 | 4 | |a pathogenesis | |
| 650 | 4 | |a protein NEDDylation | |
| 650 | 4 | |a therapy | |
| 650 | 4 | |a tumor microenvironment | |
| 700 | 1 | |a Lee-Law, Pui Yuen |e verfasserin |4 aut | |
| 700 | 1 | |a Fernandez-Barrena, Maite G |e verfasserin |4 aut | |
| 700 | 1 | |a Alvarez, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Cadamuro, Massimiliano |e verfasserin |4 aut | |
| 700 | 1 | |a Azkargorta, Mikel |e verfasserin |4 aut | |
| 700 | 1 | |a O'Rourke, Colm J |e verfasserin |4 aut | |
| 700 | 1 | |a Caballero-Camino, Francisco J |e verfasserin |4 aut | |
| 700 | 1 | |a Olaizola, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Macias, Rocio I R |e verfasserin |4 aut | |
| 700 | 1 | |a Marin, Jose J G |e verfasserin |4 aut | |
| 700 | 1 | |a Serrano-Maciá, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez-Chantar, Maria L |e verfasserin |4 aut | |
| 700 | 1 | |a Avila, Matias A |e verfasserin |4 aut | |
| 700 | 1 | |a Aspichueta, Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a Calvisi, Diego F |e verfasserin |4 aut | |
| 700 | 1 | |a Evert, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Fabris, Luca |e verfasserin |4 aut | |
| 700 | 1 | |a Castro, Rui E |e verfasserin |4 aut | |
| 700 | 1 | |a Elortza, Felix |e verfasserin |4 aut | |
| 700 | 1 | |a Andersen, Jesper B |e verfasserin |4 aut | |
| 700 | 1 | |a Bujanda, Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Rodrigues, Pedro M |e verfasserin |4 aut | |
| 700 | 1 | |a Perugorria, Maria J |e verfasserin |4 aut | |
| 700 | 1 | |a Banales, Jesus M |e verfasserin |4 aut | |
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