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
AuthorsMatos, 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.
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.

Keywordscolorectal cancer; chemoprevention; aspirin; c-Myc degradation; molecular mechanisms
Year2025
JournalCells
Journal citation14 (4), p. Article 294
PublisherMultidisciplinary Digital Publishing Institute (MDPI AG)
ISSN2073-4409
Digital Object Identifier (DOI)https://doi.org/10.3390/cells14040294
PubMed ID39996767
Scopus EID2-s2.0-85218901719
PubMed Central IDPMC11854256
Open accessPublished as ‘gold’ (paid) open access
Page range1-25
FunderAgnes 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 statusPublished
Publication dates
Online17 Feb 2025
Publication process dates
Accepted23 Jan 2025
Deposited08 May 2025
Grant IDR18-176
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/).

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