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-kappaB in the absence of kinase-dependent phosphorylation. It appears that increased expression of TGase 2 is responsible for the constitutive activation of NF-kappaB 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-kappaB 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-kappaBalpha via TGase 2 inhibition, which resulted in a decrease of NF-kappaB activity in EcR293/TG cells. Furthermore, glucosamine efficiently promoted cell death via inhibiting TGase 2-mediated NF-kappaB 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.
Kim
Dae-Seok
DS
Molecular Oncology Branch, Division of Basic and Applied Sciences, Research Institute National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
Park
Kang-Seo
KS
Jeong
Kyung-Chae
KC
Lee
Byung Ii
BI
Lee
Chang-Hoon
CH
Kim
Soo-Youl
SY
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D003538:Cystamine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D005944:Glucosamine / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D016328:NF-kappa B / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010455:Peptides; D034741:RNA, Small Interfering; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D005944:Glucosamine; D003538:Cystamine