Dual targeting of wild-type p53 and gut microbiota by Magnolol represses key metabolic process and kills CRC cells

Cancer cells consume considerable glucose quantities and majorly employ glycolysis for ATP generation. This metabolic signature (the Warburg effect) allows cancer cells to channel glucose to biosynthesis to support and maintain their dramatic growth along with proliferation. Currently, our understanding of the metabolic and mechanistic implications of the Warburg effect along with its relationship with biosynthesis remains unclear. Herein, we illustrate that the tumor repressor p53 mediate Magnolol (MAG) triggers colon cancer cell apoptosis. And MAG regulates the glycolytic and oxidative phosphorylation steps through transcriptional modulation of its downstream genes TP53-induced glycolysis modulator and biosynthesis of cytochrome c oxidase, attenuating cell proliferation and tumor growth in vivo and in vitro. Meanwhile, we show that MAG cooperates with its own intestinal microflora characteristic metabolites to repress tumors, especially remarkably declined kynurenine (Kyn)/tryptophan (Trp) ratio. Besides, strong relationships of MAG influenced genes, microbiota, as well as metabolites, were explored. Therefore, we established that p53-microbiota-metabolites function as a mechanism, which enable therapy approaches against metabolism-implicated colorectal cancer, in particular MAG as a prospective candidate for treating colorectal cancer.

Automated summary

Cancer cells rely on glycolysis for energy production and use glucose for biosynthesis to sustain their rapid growth. The relationship between this metabolic characteristic (the Warburg effect) and biosynthesis is still unclear. In this study, we demonstrate that the tumor suppressor p53 mediates the apoptosis of colon cancer cells triggered by the compound Magnolol (MAG). MAG regulates glycolysis and oxidative phosphorylation by modulating the expression of its downstream genes, TP53-induced glycolysis modulator and biosynthesis of cytochrome c oxidase, leading to reduced proliferation and tumor growth. Additionally, we find that MAG, in conjunction with metabolites produced by intestinal microflora, suppresses tumors by decreasing the kynurenine/tryptophan ratio. Our findings suggest that the p53-microbiota-metabolites axis may provide a therapeutic approach for colorectal cancer, with MAG as a potential candidate.