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

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 ACC 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 siPKCa-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.