Luteolin induces G1 arrest in human nasopharyngeal carcinoma cells via the Akt-GSK-3β-Cyclin D1 pathway

Abstract

Luteolin, a plant flavonoid is known to possess multiple biological activities such as anti-inflammation, anti-allergy, anti-oxidant as well as anti-cancer. At present, the anti-proliferative potential of luteolin has not been fully understood. In this study, we focused on the effect of luteolin on cell cycle regulation in human nasopharyngeal carcinoma (NPC) cells. First, we found that luteolin inhibited cell cycle progression at G1 phase and prevented entry into S phase in a dose- and time-dependent manner. Next, it was found that luteolin treatment led to down-regulation of cyclin D1 via enhanced protein phosphorylation and proteasomal degradation, leading to reduced CDK4/6 activity and suppression of retinoblastoma protein (Rb) phosphorylation, and subsequently inhibition of the transcription factor E2F-1. In search of the molecular mechanisms underlying luteolin-mediated cyclin D1 down-regulation, it was found that luteolin was capable of suppressing Akt phosphorylation and activation, resulting in de-phosphorylation and activation of glycogen synthase kinase-3β (GSK-3β). Activated GSK-3β then targeted cyclin D1, causing phosphorylation of cyclin D1 at Thr(286) and subsequent proteasomal degradation. The above findings were reinforced by the fact that luteolin was able to abrogate the effect of insulin on the Akt/GSK-3β/Cyclin D1 pathway, resulting in suppression of insulin-induced cell proliferation. Since Akt is often over-activated in many human cancers including NPC, it is thus believed that data from this study support the potential application of luteolin as a chemotherapeutic or chemopreventive agent in human cancer.