Li_2023_Cancer.Gene.Ther_30_608

Fibroblast activation protein (FAP) is tumor-specific and plays an important role in tumorigenecity. However, agents against its enzymatic activity or extracellular presence were unsuccessful in the clinic for undefined reasons. Here we show that FAP expression is higher in advanced ovarian cancer and is only detected in invasive ovarian cancer cells. Silencing FAP induces apoptosis and FAP's enzymatic activity is dispensable for cell survival. To elucidate the cause of apoptosis, we find that NF-kappaB activity is diminished when FAP is depleted and BIRC5 (survivin) acts downstream of FAP-NF-kappaB axis to promote cell survival. To uncover the link between FAP and NF-kappaB activation, we reveal that PRKDC (DNA-PK, DNA-dependent protein kinase) forms complex with FAP and is required for NF-kappaB activation and cell survival. Remarkably, FAP-PRKDC interaction occurs only in lipid rafts, and depleting FAP prevents lipid raft localization of PRKDC. Given the known ability of PRKDC to direct NF-kappaB activation, these results suggest that FAP recruits PRKDC in lipid rafts for NF-kappaB activation. FAP's non-enzymatic role and functioning from lipid rafts for cell survival also offer an explanation on the failure of past FAP-targeted therapies. Finally, we demonstrate that EpCAM aptamer-delivered FAP siRNA impeded intraperitoneal xenograft development of ovary tumors.