Abstract
Diffuse large B-cell lymphoma (DLBCL), the most prevalent form of lymphoma, is characterized by marked tumor heterogeneity. Treatment failure in DLBCL is often driven by drug resistance, particularly to doxorubicin, and our clinical observations suggest that comorbid type 2 diabetes further increases the incidence of such resistance. However, the intrinsic mechanisms by which altered glucose metabolism modulates doxorubicin resistance in DLBCL cells remain unclear. Here, we demonstrate that aberrant glucose metabolism activates the Protein Kinase B (AKT) signaling pathway, which in turn amplifies Nuclear Factor-kappa B (NF-κB) signaling, thereby promoting doxorubicin resistance. Comparative analyses of sensitive, primary-resistant, and acquired-resistant DLBCL cell lines revealed distinct functional and pathway alterations, notably in AKT and NF-κB signaling. Experimental validation confirmed that both pathways are critical mediators of resistance: enhanced AKT activity drives downstream NF-κB activation, which boosts glycolytic capacity and enables cancer cells to survive under chemotherapeutic stress. These findings not only elucidate a metabolic mechanism of drug resistance in DLBCL but also identify AKT and NF-κB as promising therapeutic targets for overcoming both primary and acquired doxorubicin resistance.
Keywords:
AKT/NF-κB signaling pathway; DLBCL; doxorubicin resistance; glycemic metabolism; type 2 diabetes.