FAP is critical for ovarian cancer cell survival by sustaining NF-κB activation through recruitment of PRKDC in lipid rafts

Bin Li, Zuo Ding, Ozlem Calbay, Yue Li, Tao Li, Lingtao Jin, Shuang Huang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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-κB activity is diminished when FAP is depleted and BIRC5 (survivin) acts downstream of FAP-NF-κB axis to promote cell survival. To uncover the link between FAP and NF-κB activation, we reveal that PRKDC (DNA-PK, DNA-dependent protein kinase) forms complex with FAP and is required for NF-κB 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-κB activation, these results suggest that FAP recruits PRKDC in lipid rafts for NF-κB 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.

Original languageEnglish (US)
Pages (from-to)608-621
Number of pages14
JournalCancer Gene Therapy
Volume30
Issue number4
DOIs
StatePublished - Apr 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'FAP is critical for ovarian cancer cell survival by sustaining NF-κB activation through recruitment of PRKDC in lipid rafts'. Together they form a unique fingerprint.

Cite this