title: Allosteric modulation by protein kinase Cε leads to modified responses of EGF receptor towards tyrosine kinase inhibitors.
abstract: Recently, we described a novel function of over-expressed protein kinase Cε (PKCε) as a negative allosteric modulator of EGFR signalling in several head and neck squamous carcinoma (HNSCC) cell lines. Extending this work, here we present several lines of evidence for the potency of PKCε to differently modulate the efficacy of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and lapatinib. Using the HNSCC cell line FaDu as a model, we demonstrate by co-immunoprecipitation the physical association of over-expressed PKCε with the EGFR which is stabilised by gefitinib and leads to an increase in gefitinib-induced inhibition of EGFR downstream signalling and elevated EGFR-ErbB2 heterodimerisation. Cell cycle and Western blot analysis revealed that the gefitinib-induced apoptosis was enhanced whereas the pro-apoptotic effect of lapatinib that requires another EGFR conformation was reduced by PKCε. Our findings suggest that due to elevated expression PKCε may associate with the EGFR resulting in conformational changes and different allosteric modulation of the EGFR behaviour towards TKIs. This surprising capacity indicates PKCε as a novel predictive marker protein in molecular cancer therapy with EGFR tyrosine kinase inhibitors.
authors.affiliation: Center of Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Hans-Knöll-Str.2, D-07745 Jena, Germany.
authors.forename: Simona
authors.initials: S
authors.lastname: Weisheit
authors.affiliation: Center of Molecular Biomedicine, Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Hans-Knöll-Str.2, D-07745 Jena, Germany. Electronic address: Claus.Liebmann@uni-jena.de.
authors.forename: Claus
authors.initials: C
authors.lastname: Liebmann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019281:Dimerization; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D000077156:Gefitinib; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D000077341:Lapatinib; D010957:Plasmids; D011487:Protein Conformation; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000077156:Gefitinib; D000077341:Lapatinib; D051744:Protein Kinase C-epsilon; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human