Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro.

Ursolic acid (UA), a pentacyclic triterpenoid compound, has been demonstrated to have an antiproliferative effect in various tumors. We investigated the cell killing effects of UA in the human hormone refractory prostate cancer cell line, PC-3 cells. Also, the molecular mechanisms underlying its antigrowth effect were explored. We found that UA treatment in vitro can effectively inhibit PC-3 cell viability in a dose-dependent manner by inducing apoptosis, demonstrated by annexin V-FITC/propidium iodide staining. Both extrinsic and intrinsic apoptotic pathways appear to be triggered by UA treatment, because inhibiting activation of both caspase-8 and -9 could prevent UA-induced apoptosis in PC-3 cells. The c-Jun N-terminal kinase (JNK) was found to be activated, followed by Bcl-2 phosphorylation and activation of caspase-9. On the other hand, UA inhibited the Akt pathway, subsequently upregulating the expression of Fas ligand (FasL), which initiates death receptor-mediated apoptosis in PC-3 cells. Importantly, experimentally lowering FasL expression by siRNA significantly inhibited UA-induced caspase-8 activation and at least partly attenuated the consequent apoptosis, suggesting an involvement of FasL and its regulating pathway in the cell killing effect of UA. UA also inhibited cell invasion by downregulating matrix metalloproteinase-9 via inhibition of Akt in PC-3 cells. Although further evaluation of the UA effects in vivo is needed, the present results suggest the potential utility of UA as a novel therapeutic agent in advanced prostate cancer.