Extrinsic sphingosine 1-phosphate activates S1P5 and induces autophagy through generating endoplasmic reticulum stress in human prostate cancer PC-3 cells

Sphingosine 1-phosphate (SIP) is a bioactive lysophospholipid that binds to a family of G protein-coupled receptors (GPCRs), termed S1P(1)-S1P(5). Our previous study has reported that SIP induces autophagy in human prostate cancer PC-3 cell. In addition, SIP-induced autophagy plays a prosurvival role in PC-3 cells. Accumulating evidence has shown that the autophagy responses triggered by ER stress signaling have cytoprotective effects. Thus, we attempted to investigate whether SI P-induced autophagy is a result of triggering ER stress in PC-3 cells. By monitoring XBP-1 mRNA splicing, a characteristic of ER stress, we demonstrate that S1P triggers ER stress in a concentration-dependent and time-dependent manner. Moreover, DiH SIP, a membrane-nonpermeable SIP analog without intracellular effects also enhances ER stress. Meanwhile, we also show that S1P(5) is required for S1P-induced ER stress by using RNA interference experiments. Furthermore, signaling analyses revealed that PI3K, PLC, and ROS production were involved in S1P's effects on ER stress induction. On the other hand, knockdown of XBP-1 abolished SIP-induced autophagy. In summary, our results demonstrate for the first time that the extracellular S1P-triggered ER stress is responsible for autophagy induction in PC-3 cells. (C) 2013 Elsevier Inc All rights reserved.