Protein kinase C{alpha} (PKC{alpha}) has been suggested to play an important role in tumorigenesis, invasion, and metastasis. In this study, we investigated the signal pathways selectively activated by PKC{alpha} in human hepatocellular carcinoma (HCC) cells to determine the role of mitogen-activated protein kinases (MAPK) in PKC{alpha}-mediated HCC migration and invasion. A stable SK-Hep-1 cell clone (siPKC{alpha}-SK) expressing DNA-based small interfering RNA (siRNA) PKC{alpha} was established and was then characterized by cell growth, migration, and invasion. The expression of PKC{alpha} was decreased in siPKC{alpha}-SK, and cell growth, migration, and invasion were reduced. These changes were associated with the decrease in p38 MAPK phosphorylation level, but not in c-jun-NH2-kinase-1/2 (JNK-1/2) and extracellular signal-regulated kinase-1/2 (ERK-1/2). This phenomenon was confirmed in the SK-Hep-1 cells treated with antisense PKC{alpha} olignucleotide. The p38 MAPK inhibitor SB203580 or dominant negative p38 mutant plasmid (DN-p38) was used to evaluate the dependency of p38 MAPK in PKC{alpha}-regulated migration and invasion. Attenuation of cell migration and invasion was revealed in the SK-Hep-1 cells treated with the SB203580 or DN-p38, but not with ERK-1/2 inhibitor PD98059 or JNK-1/2 inhibitor SP600125. Overexpression of constitutively active MKK6 or PKC{alpha} may restore the inactivation of p38 and the attenuation of cell migration and invasion in siPKC{alpha}-SK. Similar findings were observed in the stable HA22T/VGH cell clone expressing siRNA PKC{alpha}. This study provides new insight into the role of p38 MAPK in PKC{alpha}-mediated malignant phenotypes, especially in PKC{alpha}-mediated cancer cell invasion, which may have valuable implications for developing new therapies for some PKC{alpha}-overexpressing cancers.
