PARP9 drives the malignant progression of pancreatic cancer cells by regulating apoptosis, DNA damage, and multidrug efflux systems.

[BACKGROUND] Targeted therapy is a potent strategy for the treatment of advanced and metastatic cancers, with pancreatic cancer (PC) being one of the leading causes of cancer-related deaths worldwide. In order to resolve the limitations of existing targeted agents, there is an urgent need to find new targets and therapeutic strategies. Poly (ADP-ribose) polymerase 9 (PARP9) is aberrantly expressed in a variety of tumors. However, its relationship with PC has not been fully investigated. Lysyl oxidase like 2 (LOXL2) is potential therapeutic targets in challenging PC, which contributes to the malignant progression of PC and poor prognosis.

[METHODS] Cell lines with PARP9 knockdown or overexpression were established by lentiviral transfection, while LOXL2 was overexpressed by plasmid, and we validated the effect of PARP9 on apoptosis and DNA damage in PC cells using flow cytometry, comet assay, and western blots. The changes in downstream targets and signaling pathways after PARP9 expression changes were analyzed by RNA sequencing and protein blotting analysis. Finally, the relationship between PARP9 and LOXL2 was analyzed by immunoprecipitation, and the multidrug efflux system was determined by boinformatics analysis and western blots.

[RESULTS] PARP9 and LOXL2 were highly expressed in PC tissues and were associated with poor prognosis. PARP9 knockdown significantly inhibited the proliferation, invasion, and migration of PC cells, while also promoting apoptosis, increasing DNA damage, and inhibiting multidrug efflux systems. Meanwhile overexpression of LOXL2 reduced apoptosis and DNA damage, and drug sensitivity in PC cells caused by PARP9 knockdown. The therapeutic process of PARP9 in PC may be achieved through the synergistic action of LOXL2 and PI3K/AKT signaling pathway.

[CONCLUSION] Our study reveals a potential link between PARP9 and PC, and targeting PARP9 and LOXL2 in monotherapy or combination therapy may provide novel strategies to advanced PC.