Sustained c-Jun-NH2-Kinase Activity Promotes Epithelial-Mesenchymal Transition, Invasion, and Survival of Breast Cancer Cells by Regulating Extracellular Signal-Regulated Kinase Activation

Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA.
Molecular Cancer Research (Impact Factor: 4.38). 02/2010; 8(2):266-77. DOI: 10.1158/1541-7786.MCR-09-0221
Source: PubMed


The c-Jun NH(2)-terminus kinase (JNK) mediates stress-induced apoptosis and the cytotoxic effect of anticancer therapies. Paradoxically, recent clinical studies indicate that elevated JNK activity in human breast cancer is associated with poor prognosis. Here, we show that overexpression of a constitutively active JNK in human breast cancer cells did not cause apoptosis, but actually induced cell migration and invasion, a morphologic change associated with epithelial-mesenchymal transition (EMT), expression of mesenchymal-specific markers vimentin and fibronectin, and activity of activator protein transcription factors. Supporting this observation, mouse mammary tumor cells that have undergone EMT showed upregulated JNK activity, and the EMT was reversed by JNK inhibition. Sustained JNK activity enhanced insulin receptor substrate-2-mediated ERK activation, which in turn increased c-Fos expression and activator protein activity. In addition, hyperactive JNK attenuated the apoptosis of breast cancer cells treated by the chemotherapy drug paclitaxel, which is in contrast to the requirement for inducible JNK activity in response to cytotoxic chemotherapy. Blockade of extracellular signal-regulated kinase activity diminished hyperactive JNK-induced cell invasion and survival. Our data suggest that the role of JNK changes when its activity is elevated persistently above the basal levels associated with cell apoptosis, and that JNK activation may serve as a marker of breast cancer progression and resistance to cytotoxic drugs.

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    • "Interestingly, this difference is consistent with previously reported classifications of the chemosensitivity profiles of these three cell lines [10], suggesting that sustained ERK and c-Jun phosphorylation are involved in the cell-type specific pathways for cell migration in TT cells. Considering a positive feedback mechanism by which sustained JNK activity can promote ERK signaling through IRS-2 [14] was reported, these mechanisms may also operate in TT cell migration. By contrast, the phosphorylation of Akt was induced by EGF stimulation in EC109 cells and TT cells, but the phosphorylation levels of Akt were somewhat constant in A431 cells following EGF stimulation. "
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    • "One of the most extensively studied and well-known functions of JNK is its induction of apoptosis. Upon activation, the phosphorylated JNK translocates to nucleus where it phosphorylates and regulates the activation of transcription factors like c-Jun, ATF-2, Elk-1, p53 and c-Myc, which are involved in the induction of cell apoptosis (Dhanasekaran and Reddy, 2008; Johnson and Nakamura, 2007; Wang et al., 2010). However, it has been recently reported that the inhibition of JNK activity impairs cell migration of fibroblasts, smooth muscle cells, keratinocytes, rat bladder tumor cells, endothelial cells and Schwann cells (Chen et al., 2009; Huang et al., 2004b). "
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    • "Previous studies [1,25,30-33] indicated that HA/CD44-mediated oncogenic signaling plays an important role in the development of several solid tumors including breast cancer. Among the signaling aberrations present in breast cancer, JNK and c-Jun signaling activation appears to be one of the critical pathways for the development of breast cancer [34,35]. Gene regulation by JNK-mediated c-Jun signaling generally requires specific phosphorylation of these two molecules [36,37]. "
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