Abstract
BACKGROUND and AIMS: Pancreatic ductal adenocarcinoma (PDAC) is one of the highest mortality rate cancers with almost no curative chemotherapeutic treatment. Ferroptosis is a recently recognized regulated necrotic cell death and that has emerged to play an important role in cancer biology. Recent discoveries have highlighted the important role of Dipeptidyl-peptidase-4 (DPP4) in TP53-deficient cancer cells. PDAC Patients with a lower DPP4 level have a poorer postoperative survival. We investigated whether DPP4 contributes to ferroptosis in pancreatic cancer.
METHODS: DPP4 expression status was evaluated in PDAC tissues using tissue chip immunohistochemistry. The effects of DPP4 re-expression or knockdown on cell proliferation, the cell cycle and energy metabolism were determined. DPP4 interacting protein was identified by mass spectrometry and DPP4-related cancer pathways by RNA-seq analyses. The clinical impact of DPP4 in driving ferroptosis and enhancing gemcitabine sensitivity was assessed in patient-derived xenograft tumours (PDX), subcutaneous, and DPP4 knock-down (KD) or knock-in (KI) mice orthotopic xenograft models of PDAC.
RESULTS: DPP4 was commonly low expression in PDAC. DPP4 significantly inhibited cell proliferation by causing G1-S cell cycle arrest, inhibiting energy metabolism and promoting erastin-induced ferroptosis in vitro, and suppressed xenograft tumour growth in both subcutaneous and orthotopic xenograft mouse models (both p<0.001). Mechanistically, DPP4 facilitated ferroptosis by binding ACSL4 and the DPP4-ACSL4 interaction stabilized ACSL4 by inhibiting its ubiquitin-mediated degradation, and subsequent lipid peroxidation. This interaction inactivated their downstream key elements of NF2-YAP signalling cascades. Importantly, the DPP4-ACSL4 pathway dictated ferroptosis sensitivity and promoted the anticancer activity of gemcitabine. Activating of the DPP4-ACSL4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis in vitro and in PDX, subcutaneous, and DPP4 KD or KI orthotopic xenograft models of PDAC.
CONCLUSIONS: Collectively, these findings identify a novel role of DPP4 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance.
Citation Format: Xiang Zhou, Weiming Wang, Baofu Zhang, Zixia Lin, Yi Wang, Gang Chen. DPP4 modulates ACSL4 to promote lipid peroxidation and regulate ferroptosis in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6330.
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