Salicylate induces AMPK and inhibits c-MYC to activate a NRF2/ARE/miR-34a/b/c cascade resulting in suppression of colorectal cancer metastasis.

Autor: Liu C; Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany., Rokavec M; Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany., Huang Z; Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany., Hermeking H; Experimental and Molecular Pathology, Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-Universität München, Thalkirchner Strasse 36, D-80337, Munich, Germany. heiko.hermeking@med.uni-muenchen.de.; German Cancer Consortium (DKTK), Partner site Munich, D-80336, Munich, Germany. heiko.hermeking@med.uni-muenchen.de.; German Cancer Research Center (DKFZ), D-69210, Heidelberg, Germany. heiko.hermeking@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2023 Oct 28; Vol. 14 (10), pp. 707. Date of Electronic Publication: 2023 Oct 28.
DOI: 10.1038/s41419-023-06226-9
Abstrakt: Aspirin and its active metabolite salicylate have emerged as promising agents for the chemoprevention of colorectal cancer (CRC). Moreover, aspirin suppresses the progression of established CRCs. However, the underlying molecular mechanisms are not completely understood. Here we found that salicylate induces the expression of the miR-34a and miR-34b/c genes, which encode tumor suppressive microRNAs, in a p53-independent manner. Salicylate activated AMPK, thereby activating NRF2, which directly induced miR-34a/b/c expression via ARE motifs. In addition, salicylate suppressed c-MYC, a known repressor of NRF2-mediated transactivation, via activating AMPK. The suppression of c-MYC by salicylate was necessary for NRF2-mediated activation of miR-34a/b/c. Inactivation of miR-34a/b/c largely abrogated the inhibitory effects of salicylate on migration, invasion and metastasis formation by CRC cells. In the future, aspirin and its derivates may be used therapeutically to activate miR-34a and miR-34b/c in tumors that have lost p53.
(© 2023. The Author(s).)
Databáze: MEDLINE
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