title: Lapatinib-induced mesenchymal-epithelial transition in squamous cell carcinoma cells correlates with unexpected alteration of β-catenin expression.
abstract: The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer progression, and may promote resistance of cancer cells to therapy. Inhibiting EMT appears to be crucial to inhibit drug resistance. The mesenchymal-epithelial transition (MET), which is the reverse program of EMT in metastases, is characterized by the upregulation of epithelial adhesive proteins such as E-cadherin, and downregulation of mesenchymal proteins such as vimentin. The sensitivity of cancer cells to epithelial growth factor receptor (EGFR) inhibitor may be increased by inducing MET in these cells. Therefore, it is of clinical importance to specify the phenotype of cancer cells in order to overcome the phenomenon of drug resistance. The aim of the present study was to investigate the expression pattern of specific markers in squamous cell carcinoma (SCC) cells following stimulation with lapatinib and gefitinib. For this purpose, the head and neck (HN) SCC cell lines HNSCC22B and HNSCC11A were incubated with 0.5 and 2 µg/ml lapatinib and gefitinib, and the levels of E-cadherin, vimentin, matrix metalloproteinase-14, c-kit and β-catenin were detected by immunocytochemistry and enzyme-linked immunosorbent assay at 5, 24 and 96 h post-incubation. The results indicated that, compared with HNSCC22B cells, the protein expression levels of vimentin increased, whereas those of E-cadherin reduced, in non-stimulated HNSCC11A cells. In addition, the protein expression levels of β-catenin were altered in the epithelial- and mesenchymal-associated SCC cell lines following treatment with lapatinib and gefitinib. Furthermore, lapatinib induced the downregulation of vimentin and upregulation of E-cadherin in HNSCC11A cells in a time-dependent manner. This suggests that the sensitivity of cancer cells to lapatinib may be improved by inducing MET in these cells. In summary, the results of the present study demonstrated that lapatinib-induced MET led to an unexpected alteration of the protein expression levels of β-catenin in SCC cells. Further studies on the mechanistic role of MET are required in order to increase the sensitivity of cancer cells to EGFR inhibitor and block the EMT process in these cells.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Umbreit
authors.affiliation: Department of Urology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Faber
authors.affiliation: Department of Hematology and Oncology, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
authors.forename: Ralf-Dieter
authors.initials: RD
authors.lastname: Hofheinz
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
authors.forename: Johannes David
authors.initials: JD
authors.lastname: Schultz
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Hoermann
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Wenzel
keywords: E-cadherin; c-kit; epithelial-mesenchymal transition; gefitinib; head and neck squamous cell carcinoma; lapatinib; matrix metalloproteinase-14; mesenchymal-epithelial transition; vimentin; β-catenin