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

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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.

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Acknowledgments

We wish to thank Drs. Stuart Schreiber and Ralph Mazitschek from Dana Farber Cancer Institute (Boston, MA), and Initiative for Chemical Genetics, NIH (Bethesda, MD) for providing tubacin and niltubacin for the study and Dr. K. M. Rich, (Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, USA), for providing KCC009 compound.

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Author notes

  1. Carmine Carbone

    Present address: Digestive Molecular Clinical Oncology Research Unit, Department of Medicine, University of Verona, Verona, Italy

  2. Geny Piro

    Present address: Laboratory of Oncology and Molecular Therapy, Department of Medicine, University of Verona, Verona, Italy

Authors and Affiliations

  1. Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, 80131, Naples, Italy

    Carmine Carbone, Elena Di Gennaro & Alfredo Budillon

  2. Centro Ricerche Oncologiche Mercogliano, Istituto Nazionale Tumori Fondazione G. Pascale-IRCCS, Naples, Italy

    Geny Piro, Maria Rita Milone, Biagio Pucci & Alfredo Budillon

  3. Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy

    Michele Caraglia

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  1. Carmine Carbone
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  2. Elena Di Gennaro
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Correspondence to Alfredo Budillon.

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This study was partially supported by the following Research Grants to AB: AIRC (IG9332-2009); Italian Ministry of Health (RF-2011-02346914).

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The authors declare no additional conflict of interest.

This article does not contain any studies with human participants or animals performed by any of the authors.

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Handling Editors: S. Beninati, M. Piacentini, C. M. Bergamini.

C. Carbone and E. Di Gennaro contributed equally to this work.

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Carbone, C., Di Gennaro, E., Piro, G. et al. Tissue transglutaminase (TG2) is involved in the resistance of cancer cells to the histone deacetylase (HDAC) inhibitor vorinostat. Amino Acids 49, 517–528 (2017). https://doi.org/10.1007/s00726-016-2338-5

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