¹Department of Medical Biochemistry, Faculty of Medicine, Aydın Adnan Menderes University, Aydın, Turkey DOI : 10.29228/jrp.337 Hepatocellular carcinoma continues to be one of the major health problems. One of the most important challenges in the treatment of hepatocellular cancer is gaining resistance to chemotherapy. Therefore, there is an urgent need for discoveries of naturally occurring antitumor compounds in the diet and to elucidate the anticancer mechanisms of action of existing dietary origin compounds. Myricetin is a dietary flavonoid and its antitumor activity is reported. In this study, HepG2 cells were incubated with 100 nM rapamycin for 6 weeks to develop rapamycin resistance. 10, 100, 250 and 500 μM myricetin was applied to rapamycin resistant HepG2 human hepatocellular cancer cells (HepG2-RR) for 24 and 48 hours. Changes in ATF2, SMAD3, SMAD4 and Col1A1 expressions of HepG2-RR cells after myricetin application were evaluated by Western blot and qPCR analysis. In addition, the effect of myricetin treatment on the migration/invasion of HepG2-RR cells was specified using the BD 24-well Boyden chamber. The IC50 values of rapamycin and myricetin on HepG2 cells for 48 hours incubation was calculated as 89,03±6,14 nM and 126,25±7,32 μM, respectively. On the other hand, we found that HepG2-RR cells treated with myricetin decreased cell proliferation, invasion, and migration by reducing the expression of ATF2, SMAD3, SMAD4, and Col1A1. As a result, we were shown that myricetin administration inhibited cell growth and cell migration by suppressing ATF2 in hepatocellular carcinoma cells that gained drug resistance. Keywords : Myricetin; Rapamycin; Liver Cancer; Metastasis