Galectin-3 Identified As Key Driver Of Chemoresistance In Pancreatic Cancer

5 hours ago

Pancreatic crab is often diagnosed astatine an precocious shape and is characterized by a mediocre prognosis and rising mortality. Galectin-3 (Gal-3), a chimeric protein, plays a multifaceted domiciled successful driving nan progression of pancreatic adenocarcinoma (PAAD). While its relationship pinch tumor microenvironment cells is well-documented, nan circumstantial mechanisms by which Gal-3 mediates tumor-stromal interactions and promotes metabolic reprogramming linked to supplier guidance stay unclear.

This research, published successful nan Genes & Diseases diary by a squad from Capital Medical University, Peking University Cancer Hospital & Institute, Shandong First Medical University, and Cardiff University School of Medicine elucidates whether nan inhibition of Gal-3 look successful tumor aliases stromal cells tin amended the efficacy of gemcitabine, a modular chemotherapeutic supplier for PAAD.

Analysis of aggregate RNA sequencing nationalist datasets revealed that Gal-3 is not only remarkably up-regulated successful tumors but besides importantly associated pinch nan tumor-associated fibroblasts (TAFs) successful PAAD patients. Notably, precocious Gal-3 look correlated powerfully pinch mediocre diligent outcomes successful pancreatic cancer. Using a co-culture exemplary of PAAD cells and pancreatic stellate cells, nan researchers demonstrated that Gal-3 mediated nan Ca2+/−calcineurin-NFAT pathway to summation nan transcription of C-C motif chemokine 2 (CCL2) and basigin (BSG) successful TAFs.

Interestingly, nan Gal-3-mediated signaling cascade was shown to suppress oxidative phosphorylation successful 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 nan look of CCL2 and BSG via calcium-dependent calcineurin (CALN) dephosphorylation of atomic facet of activated T-cells 1 (NFAT1), promoting their transcription successful TAFs.

Further investigations revealed that Gal-3 enhances gemcitabine guidance via 2 mechanisms, CCL2-CCR2 signaling and nan BSG-FAK-ERK pathway. Inhibition of these pathways reversed supplier guidance and reduced tumor sphere formation. In orthotopic pancreatic xenograft models, co-treatment pinch modified citrus pectin (MCP)—a earthy Gal-3 inhibitor—and AC-73, successful operation pinch gemcitabine, importantly reduced tumor maturation without adverse effects. These findings propose that Gal-3 inhibition in vivo tin efficaciously potentiate nan anti-tumor effect of gemcitabine.

In summary, this study demonstrates that by inhibiting Gal-3 successful operation pinch gemcitabine successful nan tumor microenvironment represents a valuable invention successful nan pharmacological curen of pancreatic cancer. Overall, fixed its food-derived root and information profile, MCP presents a promising avenue for further improvement arsenic an adjunctive therapy successful pancreatic cancer.

Source:

Journal reference:

Wu, Y., et al. (2025). Galectin-3 successful tumor-stromal cells enhances gemcitabine guidance successful pancreatic adenocarcinoma by suppressing oxidative phosphorylation. Genes & Diseases. doi.org/10.1016/j.gendis.2025.101702.

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