Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase.
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.
Cohen
Ezra Eddy Wyssam
EE
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Lingen
Mark W
MW
Zhu
Bangmin
B
Zhu
Hongyan
H
Straza
Michael Wayne
MW
Pierce
Carolyn
C
Martin
Leslie E
LE
Rosner
Marsha Rich
MR
D000470:Alkaloids; D000595:Amino Acid Sequence; D053119:Benzophenanthridines; D002070:Butadienes / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009061:Mouth Mucosa / Q000201:enzymology / Q000473:pathology; D009062:Mouth Neoplasms / Q000201:enzymology / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000099221:Protein Kinase C zeta
D000470:Alkaloids; D053119:Benzophenanthridines; D002070:Butadienes; D004273:DNA, Neoplasm; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D010617:Phenanthridines; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D000099221:Protein Kinase C zeta; C113580:U 0126; C016299:chelerythrine