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Targeted Disruption of Protein Kinase C Reduces Cell Invasion and Motility through Inactivation of RhoA and RhoC GTPases in Head and Neck Squamous Cell Carcinoma

¹ Division of Hematology and Oncology, Department of Internal Medicine, ² Department of Otolaryngology, and ³ Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan

Requests for reprints: Quintin Pan, Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109. Phone: 734-647-3408; Fax: 734-615-2719; E-mail: qpan{at}med.umich.edu.

Over 70% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced stage III and IV disease. In spite of aggressive therapy, locoregional disease recurs in 60% and metastatic disease develops in 15% to 25% of patients causing a major decline in quality and length of life. Therefore, there is a need to identify and understand genes that are responsible for inducing an aggressive HNSCC phenotype. Evidence has shown that protein kinase C (PKC) is a transforming oncogene and may play a role in HNSCC progression. In this study, we determine the downstream signaling pathway mediated by PKC to promote an aggressive HNSCC phenotype. RNA interference knockdown of PKC in UMSCC11A and UMSCC36, two highly invasive and motile HNSCC cell lines with elevated endogenous PKC levels, resulted in cells that were significantly less invasive and motile than the small interfering RNA–scrambled control transfectants; 51 ± 5% (P < 0.006) and 49 ± 3% (P < 0.010) inhibition in invasion and 69 ± 1% (P < 0.0005) and 66 ± 3% (P < 0.0001) inhibition in motility, respectively. PKC-deficient UMSCC11A clones had reduced levels of active and serine-phosphorylated RhoA and RhoC. Moreover, constitutive active RhoA completely rescued the invasion and motility defect, whereas constitutive active RhoC completely rescued the invasion and partially rescued the motility defect of PKC-deficient UMSCC11A clones. These results indicate that RhoA and RhoC are downstream of PKC and critical for PKC-mediated cell invasion and motility. Our study shows, for the first time, that PKC is involved in a coordinated regulation of RhoA and RhoC activation, possibly through direct post-translational phosphorylation. (Cancer Res 2006; 66(19): 9379-84)

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