Ganoderic acid DM induces autophagic apoptosis in non-small cell lung cancer cells by inhibiting the PI3K/Akt/mTOR activity

The incidence and mortality of lung Cancer are the highest among cancer-related deaths. However, the long-term use of currently available cytotoxic drugs can increase genetic alterations in Cancer cells and cause drug-resistance, which significantly limits their usage. Since current systemic treatment options are limited, effective chemotherapeutic agents are urgently needed for non-small cell lung Cancer (NSCLC) treatment. In this study, we demonstrated that ganoderic acid DM (GA-DM) could increase Apoptosis in A549 and NCI-H460 NSCLC cells. GA-DM treatment decreased the protein expression levels of Bcl-2 and increased the expression levels of Bax, cleaved Caspase-3 and cleaved PRAP. Furthermore, GA-DM could promote autophagic flux, and the cytotoxic effect against Cancer cells of GA-DM was significantly inhibited by targeted suppression of Autophagy, suggesting that Autophagy contributed to GA-DM-induced cell death in NSCLC. Moreover, GA-DM clearly induced Autophagy by inactivating the PI3K/Akt/mTOR pathway. When overexpression of Akt reactivated Akt/mTOR pathway in A549 or NCI-H460 cells, the increase of Autophagy related marker LC3B-II and Apoptosis related protein cleaved PARP and cleaved Caspase 3 and the ration of apoptotic cells by GA-DM was reversed, suggesting that GA-DM promoted Autophagy and Apoptosis by inhibiting Akt/mTOR pathway-mediated Autophagy induction. In conclusion, our study indicated that GA-DM can induce autophagic Apoptosis in NSCLC by inhibiting Akt/mTOR activity. (209 words).