P21-Activated Protein Kinase Is Overexpressed in Hepatocellular Carcinoma and Enhances Cancer Metastasis Involving c-Jun NH2-Terminal Kinase Activation and Paxillin Phosphorylation

Abstract

Hepatocellular carcinoma (HCC) is one of the major malignancies in the world. The prognosis of HCC is poor, due to frequent intrahepatic metastasis and tumor recurrence. P21-activated protein kinase (Pak1), a main downstream effector of small Rho GTPases, Rac1 and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Here, we show that Pak1 gene was overexpressed in human HCCs. Overexpression of Pak1 in human HCCs was associated with more aggressive tumor behavior in terms of more metastatic phenotype and more advanced tumor stages. In addition, HCC cell line stably expressing Pak1 displayed increased cell motility rates and, conversely, knockdown of endogenous Pak1 expression by small interfering RNA reduced the migration rates of HCC cells. In an established metastatic HCC cell line, we found that Pak1 was overexpressed compared with its primary HCC cell line and this overexpression was associated with higher cell motility. Importantly, we found that c-Jun NH 2 -terminal kinase (JNK) was activated in HCC cell lines overexpressing Pak1. Inhibition of the JNK activity by chemical inhibitor significantly reduced the migration rates of HCC cells via attenuation of paxillin phosphorylation at Ser 178 . In conclusion, our results document that Pak1 is overexpressed in HCCs and plays an important role in the metastasis of HCC. The mechanism by which Pak1 induces cancer metastasis may involve activation of JNK and phosphorylation of paxillin. [Cancer Res 2007;67(8):3601-8]

MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells

“…However, our findings that an MLK inhibitor can block the migration of invasive breast cancer cells and that JNK inhibition blocks MLK3-induced migration in MCF-7 and MCF10A cells supports the idea that, at least in the context of breast cancer, MLK3-JNK signaling is crucial for cell migration. Indeed, a significant body of literature indicates a requirement for JNK in cancer progression (Cui et al, 2006;Ching et al, 2007;Dhillon et al, 2007;Khatlani et al, 2007;Vivanco et al, 2007;Su et al, 2009;Wagner and Nebreda, 2009).…”

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

“…PAK-1 is overexpressed in hepatocellular carcinoma, especially in the more aggressive types, and has a role in enhancing metastasis (Ching et al, 2007). The constitutive activation of PAK-1 rapidly induced breast cancer cell proliferation, and mutant kinase active T423E PAK-1 transgenic mice were found to develop hyperplasia in the mammary epithelium (Akinmade et al, 2008).…”

“…The serine/threonine kinase P-21-activated protein kinase-1 (PAK-1) is known to be involved in the development and metastasis of tumors from various tissues, including the intestine (Carter et al, 2004;Ching et al, 2007;Akinmade et al, 2008). PAK-1 was initially recognized as a downstream target of the Rho family GTPases, Rac1 and Cdc42, in regulating actin remodeling (Knaus and Bokoch, 1998;Zhou and Field, 2004;Arias-Romero and Chernoff, 2008).…”

P21-activated protein kinase 1 induces colorectal cancer metastasis involving ERK activation and phosphorylation of FAK at Ser-910

“…Moreover, Pak1 has been reported to induce proliferation, motility and invasion of these cancer cells (13)(14)(15)(16). Pak1 is believed to be involved in several cell signaling pathways, such as mitogenactivated protein kinases (MAPK) and nuclear factor-κB (NF-κB) (3,17).…”