RACK1 expression contributes to JNK activity, but JNK activity does not enhance RACK1 expression in hepatocellular carcinoma SMMC-7721 cells

Abstract

Abstract.Receptor for activated C kinase 1 (RACK1) is up-regulated in hepatocellular carcinoma (HCC) and has been reported to augment c-Jun N-terminal protein kinase (JNK) activity in HCC SMMC-7721 cells. By contrast, activator protein-1, a downstream JNK transcription factor, has been revealed to mediate the overexpression of RACK1 in melanoma cells. Therefore, the association between RACK1 and JNK activity in HCC cells has yet to be completely elucidated. The present study analyzed the effects of RACK1 or JNK loss of function on the levels of RACK1 protein, JNK activity, cell proliferation and apoptosis induced by tumor necrosis factor-related apoptosis inducing ligand in HCC SMMC-7721 cells. It was found that JNK loss of function exhibited no effect on RACK1 expression, whereas a loss of RACK1 function led to reduced JNK activity in SMMC-7721 cells. RACK1 and JNK loss of function resulted in the impaired oncogenic growth of SMMC-7721 cells. The present data further support a pivotal role of RACK1 in mediating enhanced JNK activity in HCC cells and also indicate that a novel mechanism exists for RACK1 overexpression in HCC SMMC-7721 cells. IntroductionHepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the human population, ranked the third most common cause of cancer-associated mortality worldwide, particularly in Africa and Asia (1). Although persistent viral infections and persistent exposure to hepatotoxic agents play a role in HCC neoplastic transformation (1), the underlying mechanism controlling the development and progression of HCC is largely unclear.Recently, c-Jun N-terminal protein kinase (JNK) has been reported to be involved in regulating liver tumorigenesis. JNK belongs to the mitogen-activated protein kinase (MAPK) superfamily, which also includes extracellular signal-regulated kinase (ERK) and the p38 family of kinases (2-5). The activation of JNK is mediated by sequential protein phosphorylation through a MAPK module. MAPK kinase (MKK) 7 and MKK4 play a non-redundant role in the dual phosphorylation of JNK at Thr183 and Tyr185, which is required for JNK activity (2-5). Once activated, JNK phosphorylates and activates c-Jun, a key component of the transcription factor activator protein-1 (AP-1) (2-5). Elevated levels of JNK activity have been frequently observed in HCC and have been demonstrated to contribute to HCC growth by promoting cell proliferation and resistance to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis (2-5).Receptor for activated C kinase 1 (RACK1), coded for by the GNB2L1 gene, is a scaffold protein with a propeller-like structure of seven WD40 repeats (6-10). Numerous studies have suggested that RACK1 plays a pivotal role in the coordination of cell growth, migration and differentiation during tumorigenesis (6-10). It has been demonstrated that RACK1 is up-regulated in HCC and that overexpressed RACK1 augments JNK activity, thereby promoting HCC growth by directly binding to MKK7 and enhancing MKK7 activity (11)....

Overexpression of RACK1 Promotes Metastasis by Enhancing Epithelial-Mesenchymal Transition and Predicts Poor Prognosis in Human Glioma

“…Increasing evidence indicates that RACK1 acts as a versatile signaling pathway hub, providing a platform for protein-protein interaction [10], which plays a crucial role in a diverse number of cellular biological processes, including signal transduction, virus infection, immune response, neural development, and cell differentiation [11,12,13,14]. Emerging studies show that dysregulated RACK1 is supposed to be a biomarker or regulator in a wide spectrum of human cancers [15,16,17,18,19,20,21], which implies that RACK1 could play an important role in genesis and progression [18,22] as well as resistance to chemotherapy in tumors [23]. In addition, Wang et al and Choi et al reported that overexpression of RACK1 strongly was linked with advanced clinical stage and poor prognosis in esophageal squamous cell carcinoma and non-small cell lung cancer [24,25].…”