2. Academic Validation
  3. Transcriptomics Studies Reveal Functions of Transglutaminase 2 in Breast Cancer Cells Using Membrane Permeable and Impermeable Inhibitors

Transcriptomics Studies Reveal Functions of Transglutaminase 2 in Breast Cancer Cells Using Membrane Permeable and Impermeable Inhibitors

  • J Mol Biol. 2024 May 15;436(10):168569. doi: 10.1016/j.jmb.2024.168569.
Pietro Ancona 1,  Alessandro Trentini 2,  Anna Terrazzan 3,  Silvia Grassilli 4,  Pauline Navals 5,  Eric W J Gates 6,  Valentina Rosta 7,  Carlo Cervellati 8,  Carlo M Bergamini 9,  Angela Pignatelli 10,  Jeffrey W Keillor 11,  Cristian Taccioli 12,  Nicoletta Bianchi 13
Affiliations

Affiliations

  • 1 Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy. Electronic address: pietro.ancona@unife.it.
  • 2 Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, Italy. Electronic address: alessandro.trentini@unife.it.
  • 3 Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy. Electronic address: anna.terrazzan@unife.it.
  • 4 Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, Italy. Electronic address: silvia.grassilli@unife.it.
  • 5 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Electronic address: pnavals@uottawa.ca.
  • 6 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Electronic address: egate028@uottawa.ca.
  • 7 Department of Environmental Sciences and Prevention, University of Ferrara, Ferrara, Italy. Electronic address: valentina.rosta@unife.it.
  • 8 Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy. Electronic address: carlo.cervellati@unife.it.
  • 9 Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy. Electronic address: bgc@unife.it.
  • 10 Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy. Electronic address: angela.pignatelli@unife.it.
  • 11 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada. Electronic address: jkeillor@uottawa.ca.
  • 12 Department of Animal Medicine, Production and Health, University of Padua, Padua, Italy. Electronic address: cristian.taccioli@unipd.it.
  • 13 Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy. Electronic address: nicoletta.bianchi@unife.it.
PMID: 38604527 DOI: 10.1016/j.jmb.2024.168569
Abstract

Transglutaminase 2 (TG2) performs many functions both under physiological and pathological conditions. In Cancer, its expression is associated with aggressiveness, propensity to epithelial-mesenchymal transition, and metastasis. Since TG2 performs key functions both outside and inside the cell, using inhibitors with different membrane permeability we analyzed the changes in the transcriptome induced in two triple-negative cell lines (MDA-MB-436 and MDA-MB-231) with aggressive features. By characterizing pathways and gene networks, we were able to define the effects of TG2 inhibitors (AA9, membrane-permeable, and NCEG2, impermeable) in relation to the roles of the Enzyme in the intra- and extracellular space within the context of breast Cancer. The deregulated genes revealed p53 and Integrin signaling to be the common pathways with some genes showing opposite changes in expression. In MDA-MB-436, AA9 induced Apoptosis, modulated cadherin, Wnt, Gastrin and cholecystokinin receptors (CCKR) mediated signaling, with RHOB and GNG2 playing significant roles, and affected the Warburg effect by decreasing glycolytic Enzymes. In MDA-MB-231 cells, AA9 strongly impacted HIF-mediated hypoxia, including Akt and mTOR pathway. These effects suggest an anti-tumor activity by blocking intracellular TG2 functions. Conversely, the use of NCEG2 stimulated the expression of ATP Synthase and proteins involved in DNA replication, indicating a potential promotion of cell proliferation through inhibition of extracellular TG2. To effectively utilize these molecules as an anti-tumor strategy, an appropriate delivery system should be evaluated to target specific functions and avoid adverse effects. Additionally, considering combinations with other pathway modulators is crucial.

Keywords

AA9; MDA-MB-231; MDA-MB-436; NGEG2; transglutaminase type 2.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125958
    TG2 Inhibitor