Growth inhibition of luteolin on HepG2 cells is induced via p53 and Fas/Fas-ligand besides the TGF-β pathway

Flavonoids, a class of natural polyphenolic compounds, inhibit cell cycle progression and induce apoptosis. This study was performed to investigate the antiproliferative effect of luteolin, the flavonoid isolated from Ixeris sonchifolia Hance, and to elucidate the detailed apoptotic mechanism in HCC cells. According to the result of MTT assay luteolin possessed antiproliferative effect, and HepG2 cells were the most sensitive to luteolin. Propidium iodide staining, fluorescence activated cell sorting analysis, western blot analysis and RT-PCR were applied to compare the difference of apoptotic event between the two HCC cell lines, with wild-type p53 (HepG2) or not (Hep3B) based on time and concentration. The treatment of luteolin upregulated the expression levels of transforming growth factor 31 (TGF-beta 1), p21(WAF1/CIP1), p27(KIP1), Smad4, and Fas in HCC cells. Thus, the expression of p21(WAF1/CIP1) was controlled by another factor, such as TGF-beta 1 in addition to p53, and notably the key factor might be p21(WAF1/CIP1) in the remarkable switch to G(1) cell cycle arrest in HepG2 cells rather than p27(KIP1). Luteolin induced apoptotic cell death in Hep3B cells while caused G1 arrest in HepG2 cells. Taken together, we conclude that luteolin induces apoptosis from G1 arrest via three signaling pathways of TGF-beta 1, p53, and Fas/Fas-ligand in HCC cells.