ArticleCell death discovery2025
TGM2-P2RX7 loop promotes gemcitabine resistance in pancreatic cancer by modulating glutamine metabolism and mitophagy.
Article in Cell death discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- COLEC12 promotes pancreatic cancer progression via the activation of the TGF-β signaling pathway.Molecular and cellular biochemistry · 2026Article
- Identification of prognostic genes and development of a risk model for pancreatic cancer based on hypoxia- and lipid metabolism-related genes.Discover oncology · 2026Article
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Authors and funding
6 authors.
Funding
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal type of cancer with poor diagnosis and prognosis, and overcoming gemcitabine-resistant (Gem-R) is a major obstacle in its treatment. Given the important role of glutamine (Glu) metabolism in tumor drug resistance, we investigated the role and exact mechanism of transglutaminase type 2 (TGM2) in influencing PDAC sensitivity to gemcitabine. In this study, we found that TGM2 exhibited elevated expression levels in Gem-R cells and tissue samples from patients with clinically resistant PDAC. Mechanistically, downregulation of TGM2 suppressed the proliferation of Gem-R PDAC cells both in vitro and in vivo by modulating Glu metabolism. RNA sequencing analysis revealed that the mechanism by which targeting TGM2 inhibits drug resistance in Gem-R PDAC cells may be associated with purinergic receptor P2X7 (P2RX7) within the GO:0014049 pathway (positive regulation of glutamate secretion). P2RX7 is highly expressed in Gem-R PDAC cells and tissue samples, and it participates in Glu metabolism and mitophagy in Gem-R PDAC cells. Furthermore, Glu has also been found to induce mitophagy. Lastly, TGM2 and P2RX7 form a positive feedback regulatory loop, jointly regulating Glu metabolism and mitophagy, thereby promoting drug resistance in Gem-R PDAC cells. These data suggest that the TGM2-P2RX7 loop promotes Gem-R in PDAC by improving Glu metabolism and mitophagy, highlighting its potential as a crucial therapeutic target for PDAC.
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Registered trials
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