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Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation.

ABSTRACT: 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.

SUBMITTER: Wang J

PROVIDER: S-EPMC2824784 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation.

Wang Jinhua J Kuiatse Isere I Lee Adrian V AV Pan Jingxuan J Giuliano Armando A Cui Xiaojiang X

Molecular cancer research : MCR 20100209 2

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) ...[more]

PMID: 20145041

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Project description:The expression of the c-jun proto-oncogene is rapidly induced in response to mitogens acting on a large variety of cell surface receptors. The resulting functional activity of c-Jun proteins appears to be critical for cell proliferation. Recently, we have shown that a large family of G protein-coupled receptors (GPCRs), represented by the m1 muscarinic receptor, can initiate intracellular signaling cascades that result in the activation of mitogen-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable increase in the expression of c-jun mRNA. Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promoter through MEF2 transcription factors, which do not act downstream from JNK. In view of these observations, we set out to investigate further the nature of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK-independent manner. Additionally, we demonstrated that these GPCRs can elevate the activity of novel members of the MAPK family, including ERK5, p38alpha, p38gamma, and p38delta, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38alpha and p38gamma) is necessary to fully activate the c-jun promoter. Moreover, in addition to JNK, ERK5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results suggest that the pathway linking GPCRs to the c-jun promoter involves the integration of numerous signals transduced by a highly complex network of MAPK, rather than resulting from the stimulation of a single linear protein kinase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes.

Project description:BackgroundThe objectives of this study was to explore the activation of the extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathway and osteogenesis-related factors in the subchondral bone of patients with knee osteoarthritis (OA).MethodsTen patients with primary OA who underwent total knee arthroplasty in the Department of Arthritis Surgery of our hospital were enrolled, and subchondral bone tissue samples were obtained during the operation. He staining and saffron staining were used to observe the arrangement of chondrocytes in the patient tissues. The protein expression levels of JNK, p-JNK, ERK, p-ERK, Runx2 and OMD in subchondral bone were detected by Western Blot. Knee osteoarthritis mice were established. He staining was used to observe the arrangement of subchondral bone cells in the knee joint of mice. Cellular mineralized nodules were determined by alizarin red staining.ResultsFirstly, in general and staining, it was observed that the subchondral bone lesions of knee OA participants were obvious. Compared with normal knee joints, the levels of phosphorylation-c-Jun N-terminal kinase (P-JNK) and phosphorylation-extracellular-signal-regulated kinase (P-ERK) in the subchondral bone of knee arthritis participants were significantly increased (P<0.05). The level of osteomodulin (OMD) was significantly reduced (P<0.05). Secondly, compared with normal mice, the levels of JNK, P-JNK, OMD, ERK, and P-ERK in the model group were significantly different (P<0.05). At 2-8 weeks, the JNK and P-JNK levels in the mice model group increased significantly over time (P<0.05), and the OMD level decreased significantly over time (P<0.05). The levels of ERK and P-ERK fluctuated over time. Thirdly, osteoblasts were treated with different concentrations of anisomycin, and stained with alizarin red after continuous culture for 24 and 48 h, respectively. It was found that all the cells were stained with orange-red mineralized nodules. As the concentration of anisomycin was increased, the number of cell mineralization nodules was significantly larger, and the positive rate of chemical nodules increased. Different concentrations of anisomycin were given to interfere with the osteoblasts of mice. When anisomycin was administered at a dose of 25 ng, the OMD level reached the highest level. When the concentration of anisomycin was increased, the osteocalcin (OCN) level also showed an upward trend.ConclusionsThe process by which the JNK signaling pathway regulates OMD may be closely related to the pathological changes of subchondral bone in patients with knee OA, and is involved in the occurrence and development of knee arthritis.

Project description:Extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs, or stress-activated protein kinases) are activated by diverse extracellular signals and mediate a variety of cellular responses, including mitogenesis, differentiation, hypertrophy, inflammatory reactions and apoptosis. We have examined the involvement of Ca2+ and protein kinase C (PKC) in ERK and JNK activation by the human G-protein-coupled m2 and m3 muscarinic acetylcholine receptors (mAChR) expressed in Chinese hamster ovary (CHO) cells. We show that the Ca2+-mobilizing m3 AChR is efficiently coupled to JNK and ERK activation, whereas the m2 AChR activates ERK but not JNK. Activation of JNK in CHO-m3 cells by the agonist methacholine (MCh) was delayed in onset and more sustained relative to that of ERK in either CHO-m2 or CHO-m3 cells. The EC50 values for MCh-induced ERK activation in both cell types were essentially identical and similar to that for JNK activation in CHO-m3 cells, suggesting little amplification of the response. Agonist-stimulated Ins(1,4,5)P3 accumulation in CHO-m3 cells was insensitive to pertussis toxin (PTX), consistent with a Gq/phosphoinositide-specific phospholipase C-beta mediated pathway, whereas a significant component of ERK and JNK activation in CHO-m3 cells was PTX-sensitive, indicating Gi/o involvement. Using manipulations that prevent receptor-mediated extracellular Ca2+ influx and intracellular Ca2+-store release, we also show that ERK activation by m2 and m3 receptors is Ca2+-independent. In contrast, a significant component (>50%) of JNK activation mediated by the m3 AChR was dependent on Ca2+, mainly derived from extracellular influx. PKC inhibition and down-regulation studies suggested that JNK activation was negatively regulated by PKC. Conversely, ERK activation by both m2 and m3 AChRs required PKC, suggesting a novel mechanism for PKC activation by PTX-sensitive m2 AChRs. In summary, mAChRs activate JNK and ERK via divergent mechanisms involving either Ca2+ or PKC respectively.

Dataset Information

Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation.

Publications

Sustained c-Jun-NH2-kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation.

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