ITGB4 Activates the Pentose Phosphate Pathway to Reduce the Sensitivity of Pancreatic Adenocarcinoma to Gemcitabine

BACKGROUND: Integrinβ4 (ITGB4), a transmembrane adhesion molecule, is closely associated with chemotherapy resistance in tumor cells. The pentose phosphate pathway (PPP) is a critical metabolic pathway that enables tumor cells to cope with chemotherapeutic stress and maintain survival. However, the specific mechanisms of ITGB4 regulating the PPP to influence the sensitivity of pancreatic adenocarcinoma (PAAD) to gemcitabine (GEM) remain unclear. METHODS: Data from the TCGA-PAAD dataset were utilized to assess ITGB4 expression level and its correlation with patient prognosis. The correlation between ITGB4 and the expression of key PPP genes was assessed. RT-qPCR and Western blot were employed to measure levels of ITGB4 and G6PD. The half-maximal inhibitory concentration (IC50) of GEM in cells and cell vitality were determined using the CCK-8 assay. Cell proliferation capacity was examined via the EdU assay. Glucose consumption, lactate production, and intracellular levels of NADP⁺ and NADPH were measured using specific kits to evaluate PPP metabolic activity. Intracellular reactive oxygen species (ROS) levels were detected by flow cytometry to analyze changes in the redox state. RESULTS: The high expression status of ITGB4 in PAAD was significantly linked with poor prognosis in patients, and its expression level was also positively correlated with the expression of PPP key genes. Based on functional experiment, knocking down the expression of ITGB4 significantly enhanced the sensitivity of PAAD cells to GEM. At the same time, knocking down ITGB4 resulted in significantly elevated intracellular NADPH levels and ROS levels, suggesting that the PPP pathway may be suppressed. In addition, upon 6-AN treatment, the increase in IC50 value and cell proliferation enhancement caused by overexpression of ITGB4 in GEM were reversed. CONCLUSION: ITGB4 reduces the sensitivity of PAAD cells to GEM by activating the PPP. This finding not only elucidates the mechanism of ITGB4 in PAAD chemo-resistance but also offers a theoretical basis for improving the efficacy of GEM treatment and developing targeted therapeutic strategies.