Glucosamine is an effective chemo-sensitizer via transglutaminase 2 inhibition

Aberrant increases of transglutaminase 2 (TGase 2) in tumors contribute to drug resistance. The role of TGase 2 in cancer pathogenesis was unknown until we showed that TGase 2 activates NF-κB in the absence of kinase-dependent phosphorylation. It appears that increased expression of TGase 2 is responsible for the constitutive activation of NF-κB in cancer cells. We have demonstrated that TGase 2 inhibition using siRNA, cystamine or R2 peptide promotes cell death in drug-resistant cancer cells through NF-κB inactivation. Therefore, a safe and effective small molecule for TGase 2 inhibition is being sought in the development of therapeutics for malignant cancers. By screening for TGase inhibitors in a natural compound library, we found that glucosamine has a TGase 2 inhibitory effect in vitro. Glucosamine also recovered the depletion of I-κBα via TGase 2 inhibition, which resulted in a decrease of NF-κB activity in EcR293/TG cells. Furthermore, glucosamine efficiently promoted cell death via inhibiting TGase 2-mediated NF-κB activation in drug-resistant breast cancer cells. These results suggest that glucosamine, as a TGase 2 inhibitor, might be an attractive novel target for treatment of malignant cancers.