Abstract
The CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3 or C53/LZAP) regulates apoptosis induced by genotoxic stress. Although CDK5RAP3 has been implicated in cancer progression, its exact role in carcinogenesis is not well established. In this article, we report that CDK5RAP3 has an important prometastatic function in hepatocarcinogenesis. An examination of human hepatocellular carcinoma (HCC) samples revealed at least twofold overexpression of CDK5RAP3 transcripts in 58% (39/67) of HCC specimens when compared with corresponding nontumorous livers. CDK5RAP3 overexpression was associated with more aggressive biological behavior. In HCC cell lines, stable overexpression of CDK5RAP3 promoted, and small interfering RNA-mediated knockdown inhibited, tumorigenic activity and metastatic potential. We found that overexpression of CDK5RAP3 and p21-activated protein kinase 4 (PAK4) correlated in human HCCs, and that CDK5RAP3 was a novel binding partner of PAK4, and this binding enhanced PAK4 activity. siRNA-mediated knockdown of PAK4 in CDK5RAP3-expressing HCC cells reversed the enhanced cell invasiveness mediated by CDK5RAP3 overexpression, implying that PAK4 is essential for CDK5RAP3 function. Taken together, our findings reveal that CDK5RAP3 is widely overexpressed in HCC and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation.
Highlights
The CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3, called C53/LZAP) was first identified as a binding partner of cyclin-dependent kinase 5 activator, p35nck5a, in yeast 2-hybrid screening (1)
Little information is available on how CDK5RAP3 regulates cancer metastasis, we found that CDK5RAP3 is a novel activator of p21-activated protein kinase 4 (PAK4) and activation of PAK4 can promote hepatocellular carcinoma (HCC) cell migration
CDK5RAP3 was overexpressed in human HCCs To elucidate the role of CDK5RAP3 in human HCCs, we examined CDK5RAP3 transcripts in human HCCs by using
Summary
The CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3, called C53/LZAP) was first identified as a binding partner of cyclin-dependent kinase 5 activator, p35nck5a, in yeast 2-hybrid screening (1). CDK5RAP3 has been found to be underexpressed in head and neck cancers, and forced expression of CDK5RAP3 can negatively regulate NF-kB activity (5), which. Stable overexpression of the CDK5RAP3 isoform has been shown to promote hepatocellular carcinoma (HCC) and cardiac cell proliferation (6, 7), which indicates, that CDK5RAP3 may enhance cell growth. We found that the expression of CDK5RAP3 was frequently upregulated in human HCCs at both transcript and protein levels. Little information is available on how CDK5RAP3 regulates cancer metastasis, we found that CDK5RAP3 is a novel activator of p21-activated protein kinase 4 (PAK4) and activation of PAK4 can promote HCC cell migration. We provided, in this study, a novel mechanism by which CDK5RAP3 contributes to the metastasis of HCC by activation of PAK4
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