Akebia saponin PA induces autophagic and apoptotic cell death via MTOR and MAPK pathways in gastric cancer cells

Akebia saponin PA (AS), a natural product isolated from Dipsacus asperoides, exhibits cytotoxicity in several cancer cell lines through a mechanism that is not yet defined. To better understand AS-induced cell death and its underlying mechanism, experiments were performed in human gastric cancer cells. The present studies illustrate that AS-induced cell death is caused by autophagy and apoptosis. The autophagy-inducing effect of AS was observed at an early stage, as indicated by the formation of cytoplasmic vacuoles and microtubule-associated protein 1 light chain-3 II (LC3-II) conversion while apoptosis-induction was characterized by DNA fragmentation, flow cytometric analysis, caspase-3 activation and the cleavage of poly(ADP-ribose)polymerase-1 (PARP-1). The autophagy inhibitor bafilomycin A1 decreased AS-induced cell death and caspase-3 activation, but caspase-3 inhibitor Ac-DEVD-CHO did not affect LC3-II accumulation or AS-induced cell viability, suggesting that AS induces autophagic cell death and autophagy contributes to caspase-3 mediated apoptosis. Molecular mechanism studies indicate that AS-induced autophagy is regulated by the p53/AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and Akt/mTOR signaling pathways and enhanced autophagic flux promotes mitogen-activated protein kinases (MAPKs) modulated apoptosis.