Galectin-3 identified as key driver of chemoresistance in pancreatic cancer

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Pancreatic cancer is often diagnosed at an advanced stage and is characterized by a poor prognosis and rising mortality. Galectin-3 (Gal-3), a chimeric protein, plays a multifaceted role in driving the progression of pancreatic adenocarcinoma (PAAD). While its interaction with tumor microenvironment cells is well-documented, the specific mechanisms by which Gal-3 mediates tumor-stromal interactions and promotes metabolic reprogramming linked to drug resistance remain unclear.

This research, published in the Genes & Diseases journal by a team from Capital Medical University, Peking University Cancer Hospital & Institute, Shandong First Medical University, and Cardiff University School of Medicine elucidates whether the inhibition of Gal-3 expression in tumor or stromal cells can improve the efficacy of gemcitabine, a standard chemotherapeutic agent for PAAD.

Analysis of multiple RNA sequencing public datasets revealed that Gal-3 is not only remarkably up-regulated in tumors but also significantly associated with the tumor-associated fibroblasts (TAFs) in PAAD patients. Notably, high Gal-3 expression correlated strongly with poor patient outcomes in pancreatic cancer. Using a co-culture model of PAAD cells and pancreatic stellate cells, the researchers demonstrated that Gal-3 mediated the Ca2+/−calcineurin-NFAT pathway to increase the transcription of C-C motif chemokine 2 (CCL2) and basigin (BSG) in TAFs.

Interestingly, the Gal-3-mediated signaling cascade was shown to suppress oxidative phosphorylation in tumor cells. Elevated CCL2, secreted by Gal-3-activated TAFs, inhibited NADPH oxidase 1 (NOX1) activity, reducing ROS levels, mitochondrial ATP production, and oxygen consumption. Additionally, Gal-3 induced the expression of CCL2 and BSG via calcium-dependent calcineurin (CALN) dephosphorylation of nuclear factor of activated T-cells 1 (NFAT1), promoting their transcription in TAFs.

Further investigations revealed that Gal-3 enhances gemcitabine resistance via two mechanisms, CCL2-CCR2 signaling and the BSG-FAK-ERK pathway. Inhibition of these pathways reversed drug resistance and reduced tumor sphere formation. In orthotopic pancreatic xenograft models, co-treatment with modified citrus pectin (MCP)—a natural Gal-3 inhibitor—and AC-73, in combination with gemcitabine, significantly reduced tumor growth without adverse effects. These findings suggest that Gal-3 inhibition in vivo can effectively potentiate the anti-tumor effect of gemcitabine.

In summary, this study demonstrates that by inhibiting Gal-3 in combination with gemcitabine in the tumor microenvironment represents a valuable innovation in the pharmacological treatment of pancreatic cancer. Overall, given its food-derived origin and safety profile, MCP presents a promising avenue for further development as an adjunctive therapy in pancreatic cancer.

#ResearchChemistry, #ChemicalInnovation, #Science, #ScienceResearch, #ScientificResearch, #ResearchAndDevelopment, #ChemistryEducation, #ChemistryExperiments, #ChemistryLab, #ChemistryStudents, #ChemistryStudy, #OrganicChemistry, #InorganicChemistry, #PhysicalChemistry, #AnalyticalChemistry, #Biochemistry, #MaterialsChemistry, #TheoreticalChemistry, #AppliedChemistry, #MedicinalChemistry


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