Sphingosine-1-phosphate promotes pulmonary artery smooth muscle cells proliferation by stimulating autophagy-mediated E-cadherin/CDH1 down-regulation

It has been shown that sphingosine-1-phosphate (S1P) is elevated in patients with pulmonary arterial hypertension (PAH) and promotes the proliferation of pulmonary artery smooth muscle cells (PASMCs). Meanwhile, S1P has been found to induce the activation of autophagy in several types of human diseases including cancers. However, it is still unclear whether activation of autophagy mediates S1P-induced PASMCs proliferation, and detailed mechanisms responsible for these processes are indefinite. The aims of this study are to address these issues. S1P dose- and time-dependently reduced the expression of E-cadherin/CDH1 and stimulated PASMCs proliferation; this was accompanied with the elevation of TNF receptor-associated factor 2 (TRAF2), up-regulation and ubiquitination of BECN1 and the activation of autophagy. Prior silencing TRAF2 or BECN1 using siRNA or pre-incubation of cells with autophagy inhibitor chloroquine phosphate (CQ) suppressed S1P-induced autophagy activation and subsequent CDH1 degradation and further PASMCs proliferation. Taken together, our study indicates that S1P promotes the activation of autophagy by accelerating TRAF2-mediated BECN1 up-regulation and ubiquitination, which in turn results in CDH1 reduction and contributes to PASMCs proliferation.