p38 mitogen-activated protein kinase pathway is involved in protein kinase Cα-regulated invasion in human hepatocellular carcinoma cells

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