NDLI: Tissue transglutaminase (TG2) is involved in the resistance of cancer cells to the histone deacetylase (HDAC) inhibitor vorinostat

Content Provider	Springer Nature Link
Author	Carbone, Carmine Di Gennaro, Elena Piro, Geny Milone, Maria Rita Pucci, Biagio Caraglia, Michele Budillon, Alfredo
Copyright Year	2016
Abstract	Vorinostat demonstrated preclinical and clinical efficacy in human cancers and is the first histone deacetylase inhibitor (HDACi) approved for cancer treatment. Tissue transglutaminase (TG2) is a multifunctional enzyme that catalyzes a Ca2+ dependent transamidating reaction resulting in covalent cross-links between proteins. TG2 acts also as G-protein in trans-membrane signaling and as a cell surface adhesion mediator. TG2 up-regulation has been demonstrated in several cancers and its expression levels correlate with resistance to chemotherapy and metastatic potential. We demonstrated that the anti-proliferative effect of the HDACi vorinostat is paralleled by the induction of TG2 mRNA and protein expression in cancer cells but not in ex vivo treated peripheral blood lymphocytes. This effect was also shared by other pan-HDACi and resulted in increased TG2 transamidating activity. Notably, high TG2 basal levels in a panel of cancer cell lines correlated with lower vorinostat antiproliferative activity. Notably, in TG2-knockdown cancer cells vorinostat anti-proliferative and pro-apoptotic effects were enhanced, whereas in TG2-full-length transfected cells were impaired, suggesting that TG2 could represent a mechanism of intrinsic or acquired resistance to vorinostat. In fact, co-treatment of tumor cells with inhibitors of TG2 transamidating activity potentiated the antitumor effect of vorinostat. Moreover, vorinostat-resistant MCF7 cells selected by stepwise increasing concentrations of the drug, significantly overexpressed TG2 protein compared to parental cells, and co-treatment of these cells with TG2 inhibitors reversed vorinostat-resistance. Taken together, our data demonstrated that TG2 is involved in the resistance of cancer cells to vorinostat, as well as to other HDACi.
Starting Page	517
Ending Page	528
Page Count	12
File Format	PDF
ISSN	09394451
Journal	Amino Acids
Volume Number	49
Issue Number	3
e-ISSN	14382199
Language	English
Publisher	Springer Vienna
Publisher Date	2016-10-19
Publisher Place	Vienna
Access Restriction	Subscribed
Subject Keyword	Transglutaminase-2 Vorinostat Histone deacetylase inhibitors Cancer Biochemistry Analytical Chemistry Biochemical Engineering Life Sciences Proteomics Neurobiology
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Clinical Biochemistry

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