Abstract
Cellular senescence is representing a potential anticancer therapeutic arsenal. Avenanthramide C (AVN C), as a signature compound of oats, exhibits antioxidant, anti-inflammatory, anti-atherosclerotic, and anti-tumor activities. However, the relationship between AVN C and cellular senescence in tumors remains largely unclear. Here, we elucidated that AVN C treatment predisposed colorectal cancer cells to senescent phenotype confirmed by flattened and enlarged shape characteristics, elevated senescence-associated β-galactosidase (SA-β-Gal) activity, and G1 phase arrest. Furthermore, AVN C triggered cellular senescence via transcriptionally repressing miR-183/96/182 cluster and subsequently reduced the levels of mature miR-183, −96, and −182. Mechanistically, AVN C exerted its senescence induction by attenuating β-catenin-mediated transactivation of miR-183/96/182 cluster to unleash its common target FOXO1 and two other targets, FOXO3 and SMAD4, which subsequently foster the p21 and p16 expression. In addition, AVN C is also noted to facilitate p53-mediated p21 transactivation via suppressing β-catenin. Collectively, we identified a novel mechanism of β-catenin/miR-183/96/182 cluster/FOXO1 mediated-CRC cellular senescence that entails that AVN C serves as an auxiliary agent for CRC treatment.
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