期刊
CANCER LETTERS
卷 273, 期 2, 页码 243-249出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2008.08.015
关键词
Transglutaminase 2; Drug resistance; Glucosamine; NF-kappa B; I-kappa B alpha; IKK
类别
资金
- National Cancer Center in Korea [051027 and 0810181]
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-kappa B in the absence of kinase-dependent phosphorylation. It appears that increased expression of TGase 2 is responsible for the constitutive activation of NF-kappa B 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-kappa B 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-kappa B alpha via TGase 2 inhibition, which resulted in a decrease of NF-kappa B activity in EcR293/TG cells. Furthermore, glucosamine efficiently promoted cell death via inhibiting TGase 2-mediated NF-kappa B 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. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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