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J Cancer Res Clin Oncol. 2010 Jan;136(1):143-50. doi: 10.1007/s00432-009-0645-x.

The mechanism of transglutaminase 2 inhibition with glucosamine: implications of a possible anti-inflammatory effect through transglutaminase inhibition.

Author information

1
Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, 111 Jungbalsan-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 410-769, Republic of Korea.

Abstract

PURPOSE:

Although many efforts on revealing mechanism of the constitutive activation of NF-κB in cancer cells contributed to understanding canonical pathways, largely it remains to be determined for therapeutic approaches. Recently, we found that increased expression of transglutaminase 2 (TGase 2) appears to be responsible for constitutive activation of NF-κB in certain types of cancer cells. In previous studies, we demonstrated that TGase 2 inhibition markedly increases anti-cancer drug sensitivity in drug resistance cancer cells. Therefore, we develop safe and effective TGase 2 inhibitors for therapeutic approach.

METHODS:

We screened a chemical library of natural compounds using in vitro TGase 2 activity assay. The salient discovery was that glucosamine (GlcN), a known anti-inflammatory substance, inhibited the cross-linking activity of TGase 2. We tested, through a biochemical analysis including kinetics, whether the GlcN and GlcN analogs specifically inhibit TGase 2. We also determined the inhibitory mechanism using conformational change of TGase 2.

RESULTS:

We found that the primary amine of GlcN plays a key role in TGase 2 inhibition. We also demonstrated that GlcN reversed TGase 2-mediated I-κBα polymerization in vitro. Interestingly, the metabolite of GlcN, glucosamine-6-phosphate (GlcN6P), inhibited TGase 2 activity via binding to the GTP-binding site with better efficiency than GlcN. In the native gel electrophoresis, it was clearly observed that GlcN6P binds to TGase 2 directly as an allosteric inhibitor.

CONCLUSIONS:

We concluded that GlcN inhibits TGase 2 activity by direct contact. GlcN and its metabolite GlcN6P can down-regulate constitutive activation of NF-κB in vivo via inhibition of TGase 2.

PMID:
19655169
DOI:
10.1007/s00432-009-0645-x
[Indexed for MEDLINE]

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