Effect of 2-(4”-hydroxybenzyl)-5-2”-dihydroxy-3- methoxystilbene on apoptosis and autophagic cell death of lung cancer cells

Abstract

The shifting of autophagy, a catabolic process for cell survival, toward death could be a potential mode of anti-cancer drug action. In addition, autophagic cell death (ACD) is an alternative death mechanism in resistant malignant cancer cells. This study, we demonstrated how PE5, a stilbene compound, exhibits potent ACD-promoting activity and apoptosis in lung cancer cells that may offer an opportunity for novel cancer treatment. It was found that PE5 exerted a higher toxic effect toward cancer cells compared with its effect on normal cells. Interestingly, the cell death caused by PE5 was found to be concomitant with dramatic autophagy induction as indicated by acidic vesicle staining, autophagosome and by the LC3 conversion. We further confirmed that the main death induction caused by PE5 was via ACD, since the co-treatment with an autophagy inhibitor could reverse PE5-mediated cell death. Furthermore, the defined mechanism of action and upstream regulatory signals were identified using proteomic analysis. Time-dependent proteomic analysis showed that PE5 affected 2,142 and 1,996 proteins after 12 and 24 h of treatment, respectively. Among these, the crosstalk network comprising 128 proteins that control apoptosis and 25 proteins involved in autophagy was identified. Protein–protein interaction analysis further indicated that the induction of ACD was via AKT/mTOR and Bcl-2 suppression. Western blot analysis confirmed that the active forms of AKT, mTOR and Bcl-2 were significantly decreased in PE5-treated cells. Taken together, we demonstrated the novel mechanism of PE5 in shifting autophagy toward cell death induction by targeting AKT/mTOR and Bcl-2 suppression.