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

¹ Section of Hematology/Oncology, Department of Medicine; ² Ben May Institute for Cancer Research, Center for Integrative Sciences; and ³ Department of Pathology and Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

Requests for reprints: Marsha Rich Rosner, Ben May Institute for Cancer Research, Center for Integrative Sciences, University of Chicago, 5841 South Greenwood Avenue, MC6027, Chicago, IL 60637. Phone: 312-702-0380; Fax: 312-702-4634; E-mail: mrosner{at}ben-may.bsd.uchicago.edu.

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

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