c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells

Khatlani, Tanvir; Wislez, Marie; Sun, Mianen; Honnappa, Srinivas; Iwanaga, Koichi; Ma, Long; Hanna, Amy E.; Liu, D.; Girard, Luc; Kim, Y. H.; Pollack, Jonathan R.; Minna, John D.; Wistuba, Ignacio I.; Kurie, Jonathan M.

doi:10.1038/sj.onc.1210050

Cited by 75 publications

(76 citation statements)

References 35 publications

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“…Similarly to glioblastomas (12)(13)(14)(15), aberrant activation of JNK has been observed frequently in NSCLC tumors (16,17), and a number of studies do provide evidence Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells supporting the idea that JNK has a positive role in promoting the growth of NSCLC tumors (16)(17)(18). Nevertheless, evidence…”

Section: Introductionmentioning

confidence: 89%

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

et al. 2013

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Abstract. Deregulation of c-Jun NH 2 -terminal kinase (JNK) signaling is now increasingly reported in a variety of human malignancies. Non-small cell lung cancer (NSCLC) is among such human malignancies with aberrant JNK activation; yet the exact role(s) of JNK deregulation in NSCLC biology, in particular in vivo, remains unclear. Here, we demonstrated a specific role of JNK in the control of the tumor-initiating capacity of A549 cells derived from human lung adenocarcinoma, a major subtype of NSCLC. Despite its potent inhibitory activity on A549 cell growth in vitro, SP600125, a reversible JNK inhibitor, failed to inhibit the growth of pre-established A549 xenografts in vivo when systemically administered. Nevertheless, the same SP600125 treatment caused a marked reduction in the tumor-initiating population within the A549 tumors, suggesting that JNK may be specifically required in vivo for the maintenance of the tumor-initiating population of tumor cells rather than for proliferation and survival of the entire cell population. Furthermore, A549 cells either pretreated with SP600125 or transiently transfected with siRNAs against the JNK genes in vitro showed substantially reduced ability to initiate tumor formation upon implantation into nude mice, implying that the cell intrinsic JNK activity of A549 cells is essential for the maintenance of their tumor-initiating capacity. To our knowledge, this is the first demonstration that JNK is involved in the control of the tumor-initiating capacity of NSCLC cells. Our findings also give rise to an intriguing possibility that therapies targeting JNK could contribute to prevention of relapse and/or metastasis of NSCLC through elimination of tumor-initiating cells.

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Section: Introductionmentioning

confidence: 89%

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

et al. 2013

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

2010

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The malignant phenotype in breast cancer is driven by aberrant signal transduction pathways. Mixed-lineage kinase-3 (MLK3) is a mammalian mitogen-activated protein kinase kinase kinase (MAP3K) that activates multiple MAPK pathways. Depending on the cellular context, MLK3 has been implicated in apoptosis, proliferation, migration and differentiation. Here we investigated the effect of MLK3 and its signaling to MAPKs in the acquisition of malignancy in breast cancer. We show that MLK3 is highly expressed in breast cancer cells. We provide evidence that MLK3's catalytic activity and signaling to c-jun N-terminal kinase (JNK) is required for migration of highly invasive breast cancer cells and for MLK3-induced migration of mammary epithelial cells. Expression of active MLK3 is sufficient to induce the invasion of mammary epithelial cells, which requires AP-1 activity and is accompanied by the expression of several proteins corresponding to AP-1-regulated invasion genes. To assess MLK3's contribution to the breast cancer malignant phenotype in a more physiological setting, we implemented a strategy to inducibly express active MLK3 in the preformed acini of MCF10A cells grown in 3D Matrigel. Induction of MLK3 expression dramatically increases acinar size and modestly perturbs apicobasal polarity. Remarkably, MLK3 expression induces luminal repopulation and suppresses the expression of the pro-apoptotic protein BimEL, as has been observed in Her2/Neu-expressing acini. Taken together, our data show that MLK3-JNK-AP-1 signaling is critical for breast cancer cell migration and invasion. Our current study uncovers both a proliferative and novel antiapoptotic role for MLK3 in the acquisition of a malignant phenotype in mammary epithelial cells. Thus, MLK3 may be an important therapeutic target for the treatment of invasive breast cancer.

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“…Wang et al, recently reported evidence for MKK4 having pro-oncogenic activity in an experimental setting (6). Additional evidence for a role of MKK4 in cell proliferation comes from the demonstration that the expression of a dominant-negative mutant of MKK4 in H1299 non-small-cell lung cancer (NSCLC) cells cooperated with the inhibition of the phosphatidylinositol 3-kinase signaling pathway to block cell proliferation and reduce the size of H1299 NSCLC xenograft tumors (7), whereas the overexpression of a constitutively active mutant of MKK4 in human bronchial epithelial cell lines increased their proliferation and invasive properties (17).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of mitogen-activated protein kinase kinase 4 and nuclear factor-κB in laryngeal squamous cell carcinoma: A potential indicator for poor prognosis

Chen¹

2009

Oncol Rep

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Abstract. This study aimed to investigate the expression and clinical significance of mitogen-activated protein kinase kinase 4 MKK4 and nuclear factor-κB (NF-κB) in patients with laryngeal squamous cell carcinoma (LSCC). We used immunohistochemistry (IHC) to examine the expression of MKK4 and NF-κB in 78 LSCCs and their adjacent normal tissues. To clarify the validity of MKK4 and NF-κB as determined by the IHC analysis, RT-PCR was performed on 21 tissues randomly selected from the 78 LSCCs. The positive expression rates of MKK4 and NF-κB in patients with LSCC were 67.9% (53/78) and 60.3% (47/78) respectively, which were significantly higher than those in the adjacent normal tissue (both P<0.01). The positive expression of MKK4 and NF-κB tended to be associated positively with lymph node metastasis (both P<0.01) as well as T stage (both P<0.01). The Spearman analysis indicated that the expression level of MKK4 was positively correlated with that of NF-κB significantly (rs=0.368, P<0.01). Overall survival curves estimated by Kaplan-Meier showed that tumor patients with low MKK4 and NF-κB expression in their tumor cells survive significantly longer than patients with high MKK4 and NF-κB levels (P=0.027, and P<0.01, respectively). In addition, multivariate Cox regression analysis showed that N stage, T stage and NF-κB expression are significant independent prognostic factors for overall survival (P<0.01, P=0.014, and P=0.027, respectively). These findings suggested that the expression of MKK4 and NF-κB may be considered as a useful prognostic marker of LSCC after surgical resection.

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c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells

Cited by 75 publications

References 35 publications

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

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

Overexpression of mitogen-activated protein kinase kinase 4 and nuclear factor-κB in laryngeal squamous cell carcinoma: A potential indicator for poor prognosis

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