Regulating Mitogen-Activated Protein Kinase Induced Growth of Head and Neck Tumor Cells

Protein kinase C (PKC) Z 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 PKCZ is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCZ expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCZ expression from normal to malignant tissue. PKCZ activity is required for EGF-induced extracellular signalregulated 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 mitogenactivated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCZ using either kinase-dead PKCZ mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCZ 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) PKCZ is associated with SCCHN progression, (b) PKCZ mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCZ mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCZ inhibitors function additively with other inhibitors that target similar or complementary signaling pathways. (Cancer Res 2006; 66(12): 6296-303)