Galectin-3 in tumor-stromal cells enhances gemcitabine resistance in pancreatic adenocarcinoma by suppressing oxidative phosphorylation.

Wu, Yaheng, An, Guo, Tong, J, Zhang, Wenlong, Tian, Zhihua, Dong, Bin, Liu, Xijuan, Zhao, Lin, Ye, Chunxiang, Liu, Jingtao, Zhao, Wei and Ma, Huachong 2025. Galectin-3 in tumor-stromal cells enhances gemcitabine resistance in pancreatic adenocarcinoma by suppressing oxidative phosphorylation. Genes & diseases 12 (5) , 101702. 10.1016/j.gendis.2025.101702

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Abstract

Galectin-3 (Gal-3) plays a multifaceted role in the development and progression of pancreatic adenocarcinoma (PAAD), which is associated with a poor prognosis. Its interaction with tumor microenvironment cells has been reported. However, the Gal-3-mediated tumor-stromal interaction and induced energy metabolism associated with drug resistance remain unknown. Our previous study has reported that Gal-3 secretion from tumor cells and inflammatory cytokine dependency are therapeutic targets. In this study, we revealed that the expression of Gal-3 was not only remarkably up-regulated in tumors but also significantly associated with the tumor-associated fibroblasts of PAAD patients. A coculture model of PAAD cells and pancreatic stellate cells revealed that Gal-3 mediated the Ca /-calcineurin-NFAT pathway to increase the transcription of CCL2 and BSG in tumor-associated fibroblasts. These findings ultimately lead to the observation of low energy metabolism in tumor cells. Particularly, mitochondrial oxidative phosphorylation was functionally arrested in Gal-3-high tumor cells, as demonstrated by a lower oxygen consumption rate and mitochondrial ATP production through abnormal mitochondrial morphology. The inhibition of the CCL2-CCR2 and PPIA-BSG pathways indicated the restoration of gemcitabine sensitivity when drug resistance was elicited by Gal-3. Oral administration of the natural Gal-3 inhibitor modified citrus pectin extract (MCP) showed therapeutic effect for Gal-3-activated tumors and stromal cells in orthotopic pancreatic xenograft models. Hence, our findings offer insights into the fact that low mitochondrial metabolism is dependent on Gal-3 activation-mediated gemcitabine resistance through tumor-stromal interactions. [Abstract copyright: © 2025 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltdé.]

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
ISSN:	2352-4820
Date of First Compliant Deposit:	23 July 2025
Date of Acceptance:	11 May 2025
Last Modified:	23 Jul 2025 08:30
URI:	https://orca.cardiff.ac.uk/id/eprint/179991

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