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p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer
Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRAS(G12D)-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRAS(G12D) alon...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307949/ https://www.ncbi.nlm.nih.gov/pubmed/37270580 http://dx.doi.org/10.1038/s41418-023-01168-3 |
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author | Miller, Paul Akama-Garren, Elliot H. Owen, Richard P. Demetriou, Constantinos Carroll, Thomas M. Slee, Elizabeth Al Moussawi, Khatoun Ellis, Michael Goldin, Robert O’Neill, Eric Lu, Xin |
author_facet | Miller, Paul Akama-Garren, Elliot H. Owen, Richard P. Demetriou, Constantinos Carroll, Thomas M. Slee, Elizabeth Al Moussawi, Khatoun Ellis, Michael Goldin, Robert O’Neill, Eric Lu, Xin |
author_sort | Miller, Paul |
collection | PubMed |
description | Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRAS(G12D)-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRAS(G12D) alone or KRAS(G12D) in combination with mutant p53(R172H). iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRAS(G12D)-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRAS(G12D)/iASPP(Δ8/Δ8) tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRAS(G12D) background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis. |
format | Online Article Text |
id | pubmed-10307949 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-103079492023-06-30 p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer Miller, Paul Akama-Garren, Elliot H. Owen, Richard P. Demetriou, Constantinos Carroll, Thomas M. Slee, Elizabeth Al Moussawi, Khatoun Ellis, Michael Goldin, Robert O’Neill, Eric Lu, Xin Cell Death Differ Article Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRAS(G12D)-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRAS(G12D) alone or KRAS(G12D) in combination with mutant p53(R172H). iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRAS(G12D)-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRAS(G12D)/iASPP(Δ8/Δ8) tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRAS(G12D) background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis. Nature Publishing Group UK 2023-06-03 2023-07 /pmc/articles/PMC10307949/ /pubmed/37270580 http://dx.doi.org/10.1038/s41418-023-01168-3 Text en © The Author(s) 2023 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Miller, Paul Akama-Garren, Elliot H. Owen, Richard P. Demetriou, Constantinos Carroll, Thomas M. Slee, Elizabeth Al Moussawi, Khatoun Ellis, Michael Goldin, Robert O’Neill, Eric Lu, Xin p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer |
title | p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer |
title_full | p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer |
title_fullStr | p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer |
title_full_unstemmed | p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer |
title_short | p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer |
title_sort | p53 inhibitor iaspp is an unexpected suppressor of kras and inflammation-driven pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10307949/ https://www.ncbi.nlm.nih.gov/pubmed/37270580 http://dx.doi.org/10.1038/s41418-023-01168-3 |
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