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Glucosamine is an effective chemo-sensitizer via transglutaminase 2 inhibition
Dae-Seok Kim1, Kang-Seo Park, Kyung-Chae Jeong
1Molecular Oncology Branch, Division of Basic and Applied Sciences, Research Institute National Cancer Center, Goyang, Gyeonggi-do 410-769, Republic of Korea.
Abstract:
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.
Insights
Glucosamine inhibits transglutaminase 2 (TGase 2), a protein linked to cancer drug resistance. This inhibition reduces NF-kappaB activity, promoting cancer cell death and offering a potential new cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Aberrant transglutaminase 2 (TGase 2) expression in tumors is linked to drug resistance.
- TGase 2 activates NF-kappaB signaling in cancer cells, contributing to pathogenesis.
- Targeting TGase 2 is a potential therapeutic strategy for malignant cancers.
Purpose of the Study:
- To investigate the inhibitory effect of natural compounds on TGase 2.
- To evaluate glucosamine as a TGase 2 inhibitor for cancer therapy.
- To explore the mechanism of glucosamine-induced cancer cell death.
Main Methods:
- Screening a natural compound library for TGase 2 inhibitors.
- In vitro assays to assess TGase 2 inhibitory activity of glucosamine.
- Cell-based studies in drug-resistant cancer cells to analyze NF-kappaB pathway modulation and cell death.
Main Results:
- Glucosamine demonstrated in vitro TGase 2 inhibitory effects.
- Glucosamine treatment restored I-kappaBalpha levels and decreased NF-kappaB activity.
- Glucosamine promoted cell death in drug-resistant breast cancer cells by inhibiting TGase 2-mediated NF-kappaB activation.
Conclusions:
- Glucosamine effectively inhibits TGase 2 activity.
- Glucosamine's inhibition of TGase 2-mediated NF-kappaB activation leads to cancer cell death.
- Glucosamine represents a promising novel therapeutic target for treating malignant cancers.
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