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Isorhamnetin is a flavonoid metabolite of quercetin and isolated from water dropwort (Oenanthe javanica, Umbelliferae). It has been reported that isorhamnetin exerts beneficial effects including antioxidant, anti-inflammatory, and anti-proliferative activities. The present study investigated whether the antioxidant activity of isorhamnetin is correlated with its anti-cancer effects on colorectal cancer cells. Key words colorectal cancer; hypoxia-inducible factor-1α; isorhamnetin; reactive oxygen species Isorhamnetin, a 3′-O-methylated metabolite of quercetin (Figs. 1A, B), is a flavonoid-based compound, which is extracted from Oenanthe javanica, Umbelliferae.

Compound C is a widely used chemical inhibitor that down-regulates AMP-activated protein kinase (AMPK) activity. However, it has been suggested that compound C exerts AMPK-independent effects in various cells. Here, we investigated whether compound C induces Sestrin2 (SESN2), an antioxidant enzyme induced by diverse stress. In addition, the mechanism responsible for SESN2 induction by compound C was determined. Our results showed that compound C increased SESN2 protein expression in HepG2 cells in a concentration-and time-dependent manner. The induction of SESN2 mRNA was also observed in cells treated with compound C. Increase of SESN2 luciferase activity confirmed transcriptional regulation by compound C and this substance also increased nuclear factor erythroid 2 (NF-E2)-related factor-2 (Nrf2) phosphorylation, which implies that Nrf2 was involved in SESN2 induction. Next, we sought to demonstrate whether production of reactive oxygen species (ROS) accompanied SESN2 expression. Compound C increased ROS production, but this effect was prevented by pretreatment with antioxidants or the mitochondrial complex I inhibitor. Moreover, cyclosporin A, an inhibitor of pore formation in the mitochondrial membrane, attenuated compound C-induced SESN2 induction. However, overexpression of a constitutively active form of AMPK was not able to abolish SESN2 induction by compound C, which implies that its action is independent of AMPK inhibition. In conclusion, this is the first study demonstrating that compound C alters mitochondrial function and induces ROS production, which ultimately leads to phosphorylation of Nrf2 and induction of SESN2.

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