p38 Mitogen-Activated Protein Kinase Pathway Is Involved in Protein Kinase Cα–Regulated Invasion in Human Hepatocellular Carcinoma Cells

Abstract

Protein kinase CA (PKCA) has been suggested to play an important role in tumorigenesis, invasion, and metastasis. In this study, we investigated the signal pathways selectively activated by PKCA in human hepatocellular carcinoma (HCC) cells to determine the role of mitogen-activated protein kinases (MAPK) in PKCA-mediated HCC migration and invasion. A stable SK-Hep-1 cell clone (siPKCA-SK) expressing DNA-based small interfering RNA (siRNA) PKCA was established and was then characterized by cell growth, migration, and invasion. The expression of PKCA 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-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 PKCA olignucleotide. The p38 MAPK inhibitor SB203580 or dominant negative p38 mutant plasmid (DN-p38) was used to evaluate the dependency of p38 MAPK in PKCA-regulated migration and invasion. Attenuation of cell migration and invasion was revealed in the SKHep-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 PKCA may restore the inactivation of p38 and the attenuation of cell migration and invasion in siPKCA-SK. Similar findings were observed in the stable HA22T/VGH cell clone expressing siRNA PKCA. This study provides new insight into the role of p38 MAPK in PKCA-mediated malignant phenotypes, especially in PKCA-mediated cancer cell invasion, which may have valuable implications for developing new therapies for some PKCAoverexpressing cancers. [Cancer Res 2007;67(9):4320-7]

BRCA1-IRIS overexpression abrogates UV-induced p38MAPK/p53 and promotes proliferation of damaged cells

“…It is possible that in BRCA1-IRIS-silenced cells the induction of replication arrest (ElShamy and Livingston, 2004) activates p38MAPK, as was shown recently (Im and Lee, 2008;Rodrı´guez-Bravo et al, 2007). However, in undamaged BRCA1-IRIS overexpressing cells, perhaps p38MAPK is activated to induce cell survival and/or motility (Suarez-Cuervo et al, 2004;Demuth et al, 2007;Hsieh et al, 2007;Junttila et al, 2007). Alternatively, as p-p38MAPK phosphorylates HuR in the nucleus and enhances its cytoplasmic translocation (Gorospe, 2003;Tran et al, 2003;Lafarga et al, 2009), it is possible that in undamaged cells, this is how BRCA1-IRIS induces HuR cytoplasmic translocation (this study).…”

Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected HeLa cells via enhancement of intercellular adhesion

“…For example, constitutive p38 MAPK activity has been confirmed to be crucial for the maintenance of breast cancer invasive phenotype via the stabilization of uPA and uPAR expression (25). Other studies have also revealed the positive regulatory role of p38 or ERK1/2 MAPK pathways in the invasive phenotype of human hepatocellular carcinoma cells and oral squamous cell carcinoma cells, respectively (26,27). However, cisplatin and cannabinoids have been shown to exert their anti-invasive properties on human cervical carcinoma cells (HeLa and C33A) and human lung carcinoma cells (A549) via the activation of the p38 and ERK1/2 MAPK pathways, respectively (21,12).…”

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

“…As TPA can substitute for naturally occurring diacylglycerol (DAG) for an effective activation of PKC, it is used as a classical skin tumour promoter 20 . PKCs have been implicated as mediators for MAPK/p38 activation 21,22 . In addition to mediating TPA-induced skin cancer, p38 is also critical for UV-induced skin carcinogenesis 17,23,24 .…”