Faculty Collaboration Database

Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase. Cancer Res 2006 Jun 15;66(12):6296-303

Date

06/17/2006

Pubmed ID

16778206

DOI

10.1158/0008-5472.CAN-05-3139

Scopus ID

2-s2.0-33745699726 (requires institutional sign-in at Scopus site)   70 Citations

Abstract

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

Author List

Cohen EE, Lingen MW, Zhu B, Zhu H, Straza MW, Pierce C, Martin LE, Rosner MR

Author

Michael W. Straza MD, PhD Assistant Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alkaloids
Amino Acid Sequence
Benzophenanthridines
Butadienes
Carcinoma, Squamous Cell
Cell Growth Processes
Cell Line, Tumor
Cell Transformation, Neoplastic
DNA, Neoplasm
Enzyme Activation
Epidermal Growth Factor
ErbB Receptors
Head and Neck Neoplasms
Humans
Keratinocytes
Mitogen-Activated Protein Kinases
Molecular Sequence Data
Mouth Mucosa
Mouth Neoplasms
Nitriles
Phenanthridines
Protein Kinase C
Protein Kinase Inhibitors