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Related Concept Videos

Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...

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

Pietro Ancona1, Alessandro Trentini2, Anna Terrazzan1

  • 1Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.

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|April 11, 2024
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Transglutaminase 2 (TG2) inhibitors show differential effects based on cell location. Membrane-permeable inhibitors block cancer cell growth, while impermeable ones may promote proliferation, necessitating targeted delivery strategies.

Keywords:
AA9MDA-MB-231MDA-MB-436NGEG2transglutaminase type 2

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Transglutaminase 2 (TG2) is implicated in cancer aggressiveness, epithelial-mesenchymal transition, and metastasis.
  • TG2 exerts critical functions both intracellularly and extracellularly.
  • Understanding TG2's dual role is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To analyze transcriptome changes induced by TG2 inhibitors with varying membrane permeability in triple-negative breast cancer cell lines.
  • To differentiate the effects of intracellular versus extracellular TG2 inhibition.
  • To evaluate TG2 inhibitors as a potential anti-tumor strategy.

Main Methods:

  • Transcriptome analysis of MDA-MB-436 and MDA-MB-231 cells treated with membrane-permeable (AA9) and impermeable (NCEG2) TG2 inhibitors.
  • Characterization of affected pathways and gene networks.
  • Analysis of gene expression changes related to p53, integrin signaling, apoptosis, hypoxia, and metabolism.

Main Results:

  • Common pathways affected by both inhibitors include p53 and integrin signaling, with some genes showing opposing expression changes.
  • Intracellular TG2 inhibition (AA9) induced apoptosis, modulated signaling pathways, and reduced glycolytic enzymes in MDA-MB-436 cells.
  • AA9 impacted HIF-mediated hypoxia and related pathways (AKT, mTOR) in MDA-MB-231 cells, suggesting anti-tumor activity.
  • Extracellular TG2 inhibition (NCEG2) stimulated ATP synthase and DNA replication proteins, potentially promoting proliferation.

Conclusions:

  • TG2 inhibitors exhibit distinct effects depending on their ability to penetrate cell membranes, targeting intracellular or extracellular enzyme functions.
  • Blocking intracellular TG2 shows anti-tumor potential, while inhibiting extracellular TG2 may promote cell proliferation.
  • Targeted delivery systems and combination therapies are essential for effective and safe utilization of TG2 inhibitors in cancer treatment.