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Metabolic characterisation of transglutaminase 2 inhibitor effects in breast cancer cell lines
Mariana Gallo1, Elena Ferrari1, Anna Terrazzan2
1Department of Medicine and Surgery, University of Parma, Italy.
Abstract:
Transglutaminase 2 (TG2), which mediates post-translational modifications of multiple intracellular enzymes, is involved in the pathogenesis and progression of cancer. We used 1 H-NMR metabolomics to study the effects of AA9, a novel TG2 inhibitor, on two breast cancer cell lines with distinct phenotypes, MCF-7 and MDA-MB-231. AA9 can promote apoptosis in both cell lines, but it is particularly effective in MD-MB-231, inhibiting transamidation reactions and decreasing cell migration and invasiveness. This metabolomics study provides evidence of a major effect of AA9 on MDA-MB-231 cells, impacting glutamate and aspartate metabolism, rather than on MCF-7 cells, characterised by choline and O-phosphocholine decrease. Interestingly, AA9 treatment induces myo-inositol alteration in both cell lines, indicating action on phosphatidylinositol metabolism, likely modulated by the G protein activity of TG2 on phospholipase C. Considering the metabolic deregulations that characterise various breast cancer subtypes, the existence of a metabolic pathway affected by AA9 further points to TG2 as a promising hot spot. The metabolomics approach provides a powerful tool to monitor the effectiveness of inhibitors and better understand the role of TG2 in cancer.
Insights
A novel transglutaminase 2 (TG2) inhibitor, AA9, effectively reduces breast cancer cell migration and invasiveness. Metabolomics reveals AA9 impacts glutamate and aspartate metabolism in MDA-MB-231 cells, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Oncology
- Metabolomics
Background:
- Transglutaminase 2 (TG2) plays a role in cancer progression.
- TG2 mediates post-translational modifications impacting cellular functions.
- Targeting TG2 is a potential strategy for cancer therapy.
Purpose of the Study:
- To investigate the effects of a novel TG2 inhibitor, AA9, on breast cancer cell lines.
- To analyze metabolic changes induced by AA9 using 1H-NMR metabolomics.
- To understand the role of TG2 in breast cancer pathogenesis and treatment response.
Main Methods:
- Utilized 1H-NMR metabolomics to study AA9 effects on MCF-7 and MDA-MB-231 breast cancer cells.
- Assessed cell apoptosis, migration, and invasiveness following AA9 treatment.
- Analyzed specific metabolic pathway alterations in response to TG2 inhibition.
Main Results:
- AA9 promoted apoptosis in both cell lines, with greater efficacy in MDA-MB-231 cells.
- AA9 inhibited transamidation reactions, decreasing cell migration and invasiveness in MDA-MB-231 cells.
- Metabolomics revealed distinct impacts: glutamate/aspartate metabolism in MDA-MB-231 and choline/O-phosphocholine decrease in MCF-7 cells.
- Myo-inositol alterations in both cell lines suggest an effect on phosphatidylinositol metabolism via TG2-modulated phospholipase C activity.
Conclusions:
- AA9 demonstrates significant anti-cancer effects, particularly in MDA-MB-231 cells, by targeting TG2.
- Metabolomics provides insights into TG2 inhibitor mechanisms and identifies key metabolic pathways affected by AA9.
- TG2 is a promising therapeutic target in breast cancer, and metabolomics is a valuable tool for evaluating inhibitor efficacy.
