Salicylate-elicited activation of AMP-activated protein kinase directly triggers degradation of C-Myc in colorectal cancer cells
Journal article
Matos, Ana Laura S. A., Ovens, Ashley J., Jakobsen, Emil, Iglesias-Gato, Diego, Bech, Jacob M., Friis, Stine, Bak, Lasse Kristoffer, Madsen, Gunvor I., Oakhill, Jonathan S., Puustinen, Pietri and Moreira, José M. A.. (2025). Salicylate-elicited activation of AMP-activated protein kinase directly triggers degradation of C-Myc in colorectal cancer cells. Cells. 14(4), p. Article 294. https://doi.org/10.3390/cells14040294
Authors | Matos, Ana Laura S. A., Ovens, Ashley J., Jakobsen, Emil, Iglesias-Gato, Diego, Bech, Jacob M., Friis, Stine, Bak, Lasse Kristoffer, Madsen, Gunvor I., Oakhill, Jonathan S., Puustinen, Pietri and Moreira, José M. A. |
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Abstract | Aspirin has consistently shown preventive effects in some solid cancers, notably colorectal cancer. However, the precise molecular mechanisms underlying this positive effect have remained elusive. In this study, we used an azoxymethane-induced mouse model of colon carcinogenesis to identify aspirin-associated molecular alterations that could account for its cancer-preventive effect. Transcriptomic analysis of aspirin-treated mice showed a strong reduction in c-Myc protein levels and effects on the Myc-dependent transcriptional program in colonic cells. Proto-oncogene c-Myc cooperates with AMP-activated protein kinase (AMPK) to control cellular energetics. Here, we show that salicylate, the active metabolite of aspirin, reduces c-Myc protein expression levels through multiple mechanisms that are both AMPK dependent and independent. This effect is cell-type dependent and occurs at both the transcriptional and post-translational levels. Salicylate-induced AMPK activation leads to the phosphorylation of c-Myc at Thr400, as well as its destabilization and degradation. Our results reveal a complex, multilayered, negative effect of salicylate on c-Myc protein abundance and suggest that chronic depletion of c-Myc can counteract the neoplastic transformation of colorectal epithelium, underpinning the preventive effect of aspirin on colorectal cancer. |
Keywords | colorectal cancer; chemoprevention; aspirin; c-Myc degradation; molecular mechanisms |
Year | 2025 |
Journal | Cells |
Journal citation | 14 (4), p. Article 294 |
Publisher | Multidisciplinary Digital Publishing Institute (MDPI AG) |
ISSN | 2073-4409 |
Digital Object Identifier (DOI) | https://doi.org/10.3390/cells14040294 |
PubMed ID | 39996767 |
Scopus EID | 2-s2.0-85218901719 |
PubMed Central ID | PMC11854256 |
Open access | Published as ‘gold’ (paid) open access |
Page range | 1-25 |
Funder | Agnes and Poul Friis Foundation |
Danish Cancer Society | |
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil | |
Sino-Danish Center for Education and Research | |
Aage and Johanne Louis-Hansens Foundation | |
Novo Nordisk Foundation | |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 17 Feb 2025 |
Publication process dates | |
Accepted | 23 Jan 2025 |
Deposited | 08 May 2025 |
Grant ID | R18-176 |
A11865 | |
R40-A1793 | |
R167-A11061 | |
0602-02707B | |
12OC0001341 | |
Additional information | © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
https://acuresearchbank.acu.edu.au/item/91vz8/salicylate-elicited-activation-of-amp-activated-protein-kinase-directly-triggers-degradation-of-c-myc-in-colorectal-cancer-cells
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Publisher's version
OA_Matos_2025_Salicylate_elicited_activation_of_AMP_activated.pdf | |
License: CC BY 4.0 | |
File access level: Open |
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