Co-treatment of prostate cancer cells with MSCs expressing TRAIL and IAP inhibitors reduce TRAIL resistance and production of TRAIL-induced cytokines

Prostate cancer is a malignant disease, which is the second leading cause of death of men in the UK. Cell therapy is a promising new treatment option for prostate cancer. With the discovery of a series of features of mesenchymal stem cells (MSCs), such as that they have the potential to deliver therapeutic genes in various tumour models, they are now on the verge of being tested in the clinic. TNF-related apoptosis-inducing ligand (TRAIL) as a gene therapeutic payload in MSCs is a powerful method to induce apoptosis in cancer cells including advanced stage of prostate cancer. However, we discovered that TRAIL does induces the expression of pro-metastatic cytokines, such as IL-6 and CXCL5/ENA-78, in PC3 and DU145 prostate cancer cells, but this effect could be overcome through combination treatment with an AKT inhibitor, NF-κB inhibitors or the IAP inhibitor BV6. I could demonstrate that TRAIL can induce the expression of IL-6 through the NF-κB, JNK and p38 pathways, whereas the expression of CXCL5/ENA-78 is only mediated by NF-κB. These results show that, TRAIL including TRAIL delivered by MSCs combined with small-molecule drugs, such as AKT or IAP inhibitors, not only provide a way of sensitising cancer cells to TRAIL-induced apoptosis, but also reduce the issue of side-effect-causing cytokine production. We expect this therapeutic strategy could be a promising novel targeted treatment option for prostate cancer patients.