ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
This article is part of the Research TopicInnovative Approaches to Combat Tumorigenesis and Drug Resistance: From Molecular Insights to Therapeutic AdvancementsView all 4 articles
PARP9 drives the malignant progression of pancreatic cancer cells by regulating apoptosis, DNA damage, and multidrug efflux systems
Provisionally accepted
- Lanzhou University, Lanzhou, China
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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.
Keywords: Pancreatic Cancer, Parp9, LOXL2, targeted therapy, multidrug efflux systems
Received: 28 Aug 2025; Accepted: 10 Nov 2025.
Copyright: © 2025 Wang, Liu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yulan Li, liyul@lzu.edu.cn
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