Sphingosylphosphorylcholine (SPC) is a bioactive lipid mediated popular cell apoptosis in cancer cells. As a cell-specific sphingolipid, its function in lung cancer cells is unknown. Here we showed that SPC treatment triggered necrosis and autophagy but inhibited apoptosis in two non-small cell lung cancer cell lines: A549 cell line and H157 cell line. Then 3-methyladenine (3-MA), an autophagy inhibitor, was introduced to clarify the relationships between autophagy and necrosis or apoptosis. 3MA suppressed the survival furtherly by promoting apoptosis while had no influence on necrosis. Subsequent studies revealed that activity of MKT and mammalian target of rapamycin (mTOR) complex I (mTORC1) were downregulated during autophagy. Furthermore, SPC failed to promote autophagy in p53 deleted cells. Thus SPC induced autophagy in non-small cell lung cancer cells was through AKT/mTORC1 and P53 signal pathway. Besides, SPC reduced both the mitochondria membrane potential and ROS level in A549 cells. These findings provided a molecular basis of SPC-stimulated A549 cell death and support the notion that inhibition of autophagy is likely a novel anticancer mechanism. (C) 2014 Elsevier Inc. All rights reserved.