HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT

Francesca Bruzzese, Alessandra Leone, Monia Rocco, Carmine Carbone, Geny Piro, Michele Caraglia, Elena Di Gennaro, Alfredo Budillon

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Potentiation of epidermal growth factor receptor (EGFR) inhibitors is required in squamous cell carcinoma of head and neck (SCCHN) to improve their therapeutic index. We demonstrated that the histone deacetylase inhibitor vorinostat in combination with the EGFR tyrosine kinase inhibitor gefitinib induced synergistic inhibition of proliferation, migration, and invasion as well as induction of apoptosis in SCCHN cells, including cells resistant to gefitinib. We provided evidence suggesting that differential modulation of ErbB receptors together with reversion of epithelial-to-mesenchymal transition (EMT) by vorinostat represent mechanistic bases for the observed synergism. We demonstrated in epithelial CAL27 cells expressing EGFR, ErbB2, and ErbB3 that vorinostat downregulated the expression and signaling of all three receptors. In gefitinib-resistant KB and Hep-2 cells, both of which had undergone EMT and expressed very low levels of ErbB3, vorinostat reverted the mesenchymal phenotype by inducing both E-cadherin and ErbB3 and downregulating vimentin as well as EGFR and ErbB2. Both transcriptional and post-translational mechanisms were involved in the modulation of ErbB receptors by vorinostat. Attenuation of all ErbB transcripts in CAL27 cells as well as induction of ErbB3 transcript in Hep-2 and KB cells was seen upon vorinostat treatment. We showed that vorinostat induced ubiquitination of EGFR and ErbB2 and targeted them predominantly to lysosome-degradation in all cell lines, while the induction of ErbB3-ubiquitination in CAL27 cells led to proteasomes-degradation. Overall, this study suggests that the vorinostat/gefitinib combination represents a promising therapeutic strategy that warrants further clinical evaluation in SCCHN, including tumors intrinsically resistant to EGFR-inhibitors.

Original languageEnglish
Pages (from-to)2378-2390
Number of pages13
JournalJournal of Cellular Physiology
Volume226
Issue number9
DOIs
Publication statusPublished - Sep 2011

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Histone Deacetylase Inhibitors
Epithelial-Mesenchymal Transition
Epidermal Growth Factor Receptor
Ubiquitination
Down-Regulation
Modulation
KB Cells
Degradation
gefitinib
ErbB Receptors
vorinostat
Carcinoma, squamous cell of head and neck
Epithelial Cells
Vimentin
Proteasome Endopeptidase Complex
Cadherins
Lysosomes
Protein-Tyrosine Kinases
Tumors
Cells

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Physiology

Cite this

HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. / Bruzzese, Francesca; Leone, Alessandra; Rocco, Monia; Carbone, Carmine; Piro, Geny; Caraglia, Michele; Di Gennaro, Elena; Budillon, Alfredo.

In: Journal of Cellular Physiology, Vol. 226, No. 9, 09.2011, p. 2378-2390.

Research output: Contribution to journalArticle

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