PAFAH1B1 stabilization, through PUM2-mediated competitive binding with miRNAs on its' 3'-UTR, takes active actions on ferroptosis to overcome the radioresistance to 125I radioactive particles of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic cancer is one of the most fatal malignancies with the lowest 5-year survival worldwide. Radioresistance remains the major challenge for pancreatic cancer treatment. The aim of this study is to unravel the mechanism underlying PAFAH1B1-regulated radiosensitivity in pancreatic ductal adenocarcinoma (PDAC).

METHODS: Immunohistochemistry (IHC), western blot or qRT-PCR were employed to detect the expression of PAFAH1B1, PUM2 and other molecules. Two radiation-resistant (RR) PDAC cell lines and a xenograft mouse model were established. CCK-8, colony formation assays and flow cytometry analysis were used to assess cell proliferation and apoptosis in PDAC cells, respectively. Ferroptosis was evaluated using commercial kits and BODIPY 581/591 C11 staining. The association between PUM2 and PAFAH1B1 3'UTR, as well as between miR-421/miR-301a-3p and PAFAH1B1 3'UTR, were detected by luciferase and RNA immunoprecipitation (RIP) assays.

RESULTS: PAFAH1B1 was downregulated in PDAC, and it was associated with unfavorable prognosis and radiotherapy response of PDAC patients. PAFAH1B1 overexpression enhanced the radiosensitivity to 125I particle in BxPC-3-RR, PANC-1-RR cells and PANC-1-RR xenograft tumors. Overexpression of PAFAH1B1 potentiated radiation-impaired cell viability and proliferation via triggering ferroptosis in PDAC cells. Mechanistically, PUM2 increased PAFAH1B1 expression via competitively binding to PAFAH1B1 3'UTR with miR-421 and miR-301a-3p. Moreover, PUM2 promoted radiation-induced ferroptosis in a PAFAH1B1-dependent manner.

CONCLUSION: PUM2/PAFAH1B1 axis decreased the radioresistance to 125I radioactive particles in PDAC via triggering ferroptosis.