MMR-PI3KAkt and ERK-lung cancer--2012.pdfVIP

MOLECULAR MEDICINE REPORTS 5: 1256-1260, Abstract. Sinomenine (SIN) is a bioactive component derived from a Chinese medicinal plant. Our previous studies demon- strated that SIN has cytotoxic effects on human lung cancer cells. However, the antitumor molecular mechanisms of SIN have yet to be elucidated in detail. In the present study, we further explored the effects of SIN on NCI-H460 human lung cancer cell viability and apoptosis and investigated the regula- tion and function of PI3K/Akt and ERK signaling pathways during SIN-induced apoptosis in various lung cancer cell lines. NCI-H460 cells were incubated with 200 μg/ml SIN for the indicated times (0, 24, 48 or 72 h). Cell viability was assessed by MTT assay. Akt, p-Akt, ERK1/2 and p-ERK1/2 protein levels were detected by western blotting, respectively. Two different selective inhibitors (LY294002 for the PI3K pathway; PD98059 for the MEK/ERK pathway) were used to characterize the relative roles of PI3K/Akt and ERK in SIN-induced apoptosis. Apoptosis was determined by flow cytometry. SIN inhibited the proliferation of NCI-H460 cells in a time-dependent manner, which was accompanied with significant activation of pAkt and pERK. LY294002 and PD98059 both significantly increased SIN-induced apoptosis in NCI-H460, NCI-H226 and NCI-H522 cells. Our findings suggest that the activation of the PI3K/Akt and ERK signaling pathways antagonize SIN-induced lung cancer cell apoptosis and molecules that inhibit these pathways should potentiate the effects of SIN. This study represents a significant step forward in our understanding of the signal transduction path- ways associated with the apoptosis elicited by SIN. Introduction The alkaloid sinomenine (7,8-didehydro-4-hydroxy-3,7- dimethoxy-17-methyl-9α,13α,14α-morphinan-6-one) (SIN) is a bioactive component derived from the Chinese medicinal plant Sinomenium acutum Rehd. et Wils (family Menispermaceae), which has been utilized by Chinese