Protein kinase Calpha (PKCalpha) has been suggested to play an important role in
tumorigenesis, invasion, and
metastasis. In this study, we investigated the signal pathways selectively activated by PKCalpha in human
hepatocellular carcinoma (HCC) cells to determine the role of
mitogen-activated protein kinases (MAPK) in PKCalpha-mediated HCC migration and invasion. A stable SK-Hep-1 cell clone (siPKCalpha-SK) expressing
DNA-based
small interfering RNA (
siRNA) PKCalpha was established and was then characterized by cell growth, migration, and invasion. The expression of PKCalpha was decreased in siPKCalpha-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-NH(2)-
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 PKCalpha olignucleotide. The
p38 MAPK inhibitor
SB203580 or dominant negative p38 mutant plasmid (DN-p38) was used to evaluate the dependency of
p38 MAPK in PKCalpha-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 PKCalpha may restore the inactivation of p38 and the attenuation of cell migration and invasion in siPKCalpha-SK. Similar findings were observed in the stable HA22T/VGH cell clone expressing
siRNA PKCalpha. This study provides new insight into the role of
p38 MAPK in PKCalpha-mediated malignant phenotypes, especially in PKCalpha-mediated
cancer cell invasion, which may have valuable implications for developing new
therapies for some PKCalpha-overexpressing
cancers.