PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFκB and PPARγ

Interleukin-8 (IL8/CXCL8) has been described as a key effector in prostate cancer progression and resistance to standard chemotherapeutic drugs. In the present study, we investigated the effect of the natural, angio-inhibitory and anti-tumoral Pigment Epithelium-Derived Factor (PEDF) on the expression of IL8 cytokine by prostate cancer cells. Using a cytokine antibody array and ELISA, in addition to IL8 quantitative RT PCR, we showed that PEDF inhibits the production of IL8 in human hormone-refractory prostate cancer cells, and delays the growth of these cells in vitro. IL8 reduction was mimicked in cancer cells treated with PPARγ agonist and NFκB-specific inhibitors. Accordingly, PPARγ expression increased in response to PEDF, whereas RelA/p65 expression and nuclear localization, and NFκB transcriptional activity decreased. NFκB deactivation was reversed by the PPARγ antagonist GW9662 and PPARγ (Leu468/Glu471) dominant negative suggesting a PPARγ-dependent process. We also investigated PEDF Receptor/PLA2 as key player in this pathway by small interference RNA. PEDFR knock down in prostate cancer cells reversed PEDF-induced PPARγ up-regulation, and NFκB and IL8 inhibition compared to non-targeting control siRNA. We conclude that by binding to PEDFR, PEDF up-regulates PPARγ, leading subsequently to suppressed NFκB-mediated transcriptional activation, reduced production of IL8 and limited proliferation of prostate cancer cells. These results reinforce PEDF's therapeutic potential and imply that blocking IL8 could represent a novel alternative for prostate cancer treatment.

► Molecular mechanisms involved in the inhibition of IL8 by PEDF in HRPC cells. ► Down-regulation of IL8 reduces the proliferation of HRPC cells. ► PEDF subsequently up-regulates PPARγ and inactivates NFκB in HRPC cells. ► PPARγ and NFκB regulation by PEDF are dependent of PEDF-R. ► IL8 inhibition as a new anti-tumor modality for PEDF.