Data from Protein Kinase Cζ Mediates Epidermal Growth Factor–Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase

Protein kinase C (PKC) ζ has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCζ is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCζ expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCζ expression from normal to malignant tissue. PKCζ activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCζ using either kinase-dead PKCζ mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCζ inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCζ is associated with SCCHN progression, (b) PKCζ mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCζ mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCζ inhibitors function additively with other inhibitors that target similar or complementary signaling pathways. (Cancer Res 2006; 66(12): 6296-303)