Abstract 5233: Increased galectin-3 in tumor-stromal cells enhances gemcitabine resistance in pancreatic cancer via suppressing oxidated phosphorylation

Abstract Pancreatic cancer accounts for nearly about 3% of all cancer cases, which represents a relatively common malignant tumor with rising incidence and mortality rates. Our previous studies have proved that Gal-3 could increase the malignancy of tumor cells and activate collagen and fibrin crosslinking in the stroma. Besides, Gal-3 promoted stromal cells releasing a large number of inflammatory cytokines, such as IL-6 and IL-8, which accelerated tumor progression through the tumor microenvironment deterioration. Additionally, we found the modified citrus pectin (MCP), a natural inhibitor of Gal-3, could inhibit tumor growth in the mouse xenograft model of pancreatic cancer. It is providing a new idea for tumor treatment using dietary interventions. However, there are still few reports on the role of Gal-3 in chemotherapy resistance in pancreatic cancer, so in-depth exploration of this area is urgently needed. This study aims to further elaborate on whether inhibition of Gal-3 expression in tumor cells or stromal cells can be combined with gemcitabine to effectively prevent pancreatic cancer progression. We evaluated Gal-3 levels in various types of pancreatic cancer samples and subsequently established stable-transfected pancreatic cancer cell lines. Based on our previous findings, gemcitabine sensitivity in different cell lines was determined to assess the relationship between Gal-3 expression and drug resistance. The results have indicated that inhibition of Gal-3 expression may reduce the dose-dependence of pancreatic tumors on gemcitabine chemotherapy, thereby enhancing treatment efficacy. Furthermore, we explored the effects of Gal-3 on the mitochondrial oxidative phosphorylation and reactive oxygen species (ROS) levels, during the substrate end of the respiratory chain in the mitochondrial membrane in PAAD cells, and its associated pathways in gemcitabine chemotherapy. It has been demonstrated that fibroblast-induced drug-resistant tumors exhibit a significant reduction through the CCL2-CCR2 axis. This reduction occurs in a multifactorial manner, involving calcium-dependent PPIA-BSG (CD147) pathway and dephosphorylation of NFAT1 intracellular mechanisms. The consequence of such a phenomenon is that it thereby enables these cells to effectively counter the DNA damage caused by gemcitabine. Our research provides significant insights for future dietary interventions and the development of novel agents, opening new avenues for improving patient prognosis. Citation Format: Jia Tong, Guo An, Jingtao Liu, Chunxiang Ye, Huachiong Ma, Wei Zhao. Increased galectin-3 in tumor-stromal cells enhances gemcitabine resistance in pancreatic cancer via suppressing oxidated phosphorylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5233.