Protein kinase C Zeta mediates EGF-induced growth of head and neck tumor cells by regulating MAP kinase

Proc Amer Assoc Cancer Res, Volume 47, 2006 70 Protein kinase C zeta (PKCζ) has been implicated as a mediator of epidermal growth factor receptor (EGFR) and MAP kinase (ERK) signaling in epithelial cells. Since 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. 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 ERK activation in both normal adult epidermal keratinocytes and 5 of 7 SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or MAP kinase activity suppressed DNA synthesis. Consistent with this observation, transfection of SCCHN cells with a kinase-dead PKCζ construct inhibited autocrine or EGF-induced DNA synthesis. Finally, PKCζ inhibition enhanced the anti-proliferative effects of both a MEK (U0126) and a broad spectrum PKC inhibitor (chelerythrine chloride). The results indicate that 1) PKCζ is associated with SCCHN progression; 2) PKCζ mediates EGF stimulated MAP kinase activation in keratinocytes and SCCHN cell lines; 3) PKCζ mediates EGFR and MAP kinase-dependent autocrine proliferation in SCCHN cell lines; and 4) PKCζ inactivation potentiates the action of other inhibitors that target similar or complementary signaling pathways.