Allosteric modulation by protein kinase C epsilon leads to modified responses of EGF receptor towards tyrosine kinase inhibitors

作者：Weisheit Simona; Liebmann Claus^*

来源：Cellular Signalling, 2012, 24(2): 422-434.

DOI：10.1016/j.cellsig.2011.09.010

• PKC epsilon
• EGFR
• HNSCC cells
• Gefitinib
• Lapatinib
• Allosteric modulation

Recently, we described a novel function of over-expressed protein kinase C epsilon (PKC epsilon) 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 PKC epsilon 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 PKC epsilon 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 PKC epsilon. Our findings suggest that due to elevated expression PKC epsilon may associate with the EGFR resulting in conformational changes and different allosteric modulation of the EGFR behaviour towards TKIs. This surprising capacity indicates PKC epsilon as a novel predictive marker protein in molecular cancer therapy with EGFR tyrosine kinase inhibitors.

• 出版日期2012-2