Avenanthramide A Induces Cellular Senescence via miR-129-3p/Pirh2/p53 Signaling Pathway To Suppress Colon Cancer Growth

Abstract

Cellular senescence is the state of irreversible cell cycle arrest that provides a blockade during oncogenic transformation and tumor development. Avenanthramide A (AVN A) is an active ingredient exclusively extracted from oats, which possesses antioxidant, anti-inflammatory, and anticancer activities. However, the underlying mechanism(s) of AVN A in the prevention of cancer progression remains unclear. In the current study, we revealed that AVN A notably attenuated tumor formation in an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model. AVN A treatment triggered cellular senescence in human colon cancer cells, evidenced by enlarging cellular size, upregulating β-galactosidase activity, γ-H2AX positive staining, and G1 phase arrest. Moreover, AVN A treatment significantly increased the expression of miR-129-3p, which markedly repressed the E3 ubiquitin ligase Pirh2 and two other targets, IGF2BP3 and CDK6. The Pirh2 silencing by miR-129-3p led to a significant increase in protein levels of p53 and its downstream target p21, which subsequently induced cell senescence. Taken together, our data indicate that miR-129-3p/Pirh2/p53 is a critical signaling pathway in AVN A induced cellular senescence and AVN A could be a potential chemopreventive strategy for cancer treatment.

Chemopreventive Effect of the Germinated Oat and Its Phenolic-AVA Extract in Azoxymethane/Dextran Sulfate Sodium (AOM/DSS) Model of Colon Carcinogenesis in Mice

“…Studies regarding the chemopreventive effect of oat sprouts and whole oats are limited in comparison with those discussing the unique polyphenolic alkaloids-AVAs-exclusively extracted from oats, among other compounds such as steroidal saponins, β-glucan, and flavonoids [5,[9][10][11]13,15,44,45,52,[65][66][67][68], mainly through mechanisms related to their antioxidant, anti-inflammatory, immunomodulatory, antiproliferative, proapoptotic, cancer cell growth, and senescence control activities. These studies suggest that the notion of effective antitumor activity arising from whole oats may be due to the synergistic effects of multiple compounds rather than any one nutrient or compound alone.…”

“…In vitro studies indicate that AVAs prevent cancer mainly by blocking reactive species, and exhibit potential therapeutic activity through the modulation of different pathways, including the activation of apoptosis and senescence and the blocking of cell proliferation. In this context, AVA-A (2p) notably attenuated tumor formation in an azoxymethane (AOM)/dextran sulfate sodium (DSS) model, most likely through the induction of cellular senescence [15].…”

Halofuginone inhibits tumorigenic progression of 5‑FU‑resistant human colorectal cancer HCT‑15/FU cells by targeting miR‑132‑3p <em>in&nbsp;vitro</em>

“…Studies have demonstrated that natural compounds, including curcumin, tectorigenin and avenanthramide A can regulate the expression of numerous miRNAs, which increases the sensitivity of cancer cells to conventional chemotherapeutics and thereby effectively suppresses tumor cell proliferation ( 40 – 42 ). Previous studies have demonstrated that anticarcinogenic effects of HF on various types of cancer ( 43 – 45 ).…”

Overview of the Anticancer Profile of Avenanthramides from Oat

“…The induction of cellular senescence is another potential mechanism postulated for the tumor-suppressive activity of AVAs [70]. Senescence refers to the irreversible cell-cycle arrest occurring when cells are under stress conditions, such as oxidative stress, telomere shortening, genomic damages, and metabolism dysfunction.…”

“…AVA 2p triggered cellular senescence in colon cancer cells (HCT116 and HCT8), as indicated by specific morphological and biochemical features including cellular enlarged size and increased β-galactosidase activity, together with H2A.X positive staining and cell-cycle arrest in G1 phase [70]. Furthermore, AVA 2p significantly increased the expression of miR-129-3p.…”