Myricetin Induces Autophagy and Cell Cycle Arrest of HCC by Inhibiting MARCH1-Regulated Stat3 and p38 MAPK Signaling Pathways

Abstract

Myricetin is a type of natural flavonol known for its anticancer activity. However, the molecular mechanism of myricetin in anti-hepatocellular carcinoma (HCC) is not well defined. Previous studies indicated that downregulation of membrane-associated RING-CH finger protein 1 (MARCH1) contributed to the treatment of a variety of cancers. Whether the anticancer property of myricetin is associated with MARCH1 expression remains to be investigated. This research explored the anti-HCC mechanism of myricetin. Our results indicate that myricetin induces autophagy and arrests cell cycle at the G2/M phase to suppress the proliferation of HCC cells by downregulating MARCH1. Myricetin reduces MARCH1 protein in Hep3B and HepG2 cells. Interestingly, myricetin upregulates the MARCH1 mRNA level in Hep3B cells but downregulates it in HepG2 cells. The knockdown of MARCH1 by siRNAs (small interfering RNAs) decreases the phosphorylated p38 MAPK (p-p38 MAPK) and Stat3 (p-Stat3), and inhibits HCC cell viability. Moreover, myricetin inhibits p38 MAPK and Stat3 signaling pathways by downregulating MARCH1 to repress HCC growth both in vitro and in vivo. Bafilomycin A1 (BafA1), an autophagy inhibitor, has synergetic effect with myricetin to inhibit HCC growth. Taken together, our results reveal that myricetin inhibits the proliferation of HCC cells by inhibiting MARCH1-regulated p38 MAPK and Stat3 signaling pathways. This research provides a new molecular mechanism for myricetin in anti-HCC and suggests that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.