Regulation of apoptosis and autophagy by luteolin in human hepatocellular cancer Hep3B cells.
Biochem Biophys Res Commun. 2019 Oct 1 ;517(4):617-622. Epub 2019 Aug 3. PMID: 31383362
In several cancer cells, luteolin (3',4',5,7-tetrahydroxyflavone) exerts anticancer effects by upregulation of oxidative stress and endoplasmic reticulum (ER) stress, which are shown to activate p53-dependent cell death. Since luteolin-mediated ER stress regulation has not been investigated in hepatocellular carcinoma (HCC) cells, we investigated the role of ER stress in anti-carcinogenic effects using p53-wild type and p53-null HCC cells treated with luteolin. Trypan blue exclusion test was implemented to determine cell viability. Western blot was applied to compare the difference of autophagy, apoptosis, and proliferation event between cell lines. ER stress and p53 activation were determined by RT-PCR. Our results showed that luteolin at 5-10 μmol/L induced higher cytotoxicity in p53-null Hep3B cells than in p53-wild type HepG2 cells. Cytotoxicity was not observed in normal liver cells. Apoptosis activation and proliferation inhibition occurred in only p53-null Hep3B cells in response to luteolin treatment. Also, luteolin induced oxidative stress and ER stress in p53-null Hep3B cells. Although we observed the induction of p21 in Hep3B cells, the concomitant increases in mRNA levels of p53 family members, including TAp63 and TAp73, were not observed. Furthermore, luteolin induced autophagy in Hep3B cells only, which enhanced cell viability. Taken together, this study suggests that luteolin-induced ER stress may exert anticancer effects in a p53-independent manner.