Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study first investigates the anti-metastatic effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer cells, A549. First, the result demonstrated plumbagin could inhibit TPA induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and Boyden chamber assay. Data also showed plumbagin could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) involved in the down-regulating enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, plumbagin also strongly inhibited TPA-induced phosphorylation and degradation of inhibitor of kappaBalpha (IkappaBalpha), and the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1) by plumbagin treatment was further observed. Further, the treatment of specific inhibitor for ERK (U0126) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Presented data reveals that plumbagin is a novel, effective, anti-metastatic agent that functions by down-regulating MMP-2 and u-PA gene expressions.
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PMID:Plumbagin inhibits TPA-induced MMP-2 and u-PA expressions by reducing binding activities of NF-kappaB and AP-1 via ERK signaling pathway in A549 human lung cancer cells. 1976 35

Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. Emodin exhibits anticancer effects against a variety of cancer cells, including lung cancer cells. ERCC1 and Rad51 proteins are essential for nucleotide excision repair and homologous recombination, respectively. Furthermore, ERCC1 and Rad51 overexpression induces resistance to DNA-damaging agents that promote DNA double-strand breaks. Accordingly, the aim of this study was to determine the role of ERCC1 and Rad51 in emodin-mediated cytotoxicity in human non-small cell lung cancer (NSCLC) cells. Both ERCC1 and Rad51 protein levels as well as mRNA levels were decreased in four different NSCLC cell lines after exposure to emodin. These decreases correlated with the inactivation of the MKK1/2-ERK1/2 pathway. Moreover, cellular ERCC1 and Rad51 protein and mRNA levels were specifically inhibited by U0126, a MKK1/2 inhibitor. We found that transient transfection of human NSCLC cells with si-ERCC1 or si-Rad51 RNA and cotreatment with U0126 could enhance emodin-induced cytotoxicity. In contrast, overexpression of constitutively active MKK1/2 vectors (MKK1/2-CA) was shown to significantly recover reduced phospho-ERK1/2, ERCC1, and Rad51 protein levels and to rescue cell viability upon emodin treatment. These results demonstrate that activation of the MKK1/2-ERK1/2 pathway is the upstream signal regulating the expressions of ERCC1 and Rad51, which are suppressed by emodin to induce cytotoxicity in NSCLC cells.
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PMID:Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells. 1979 75

Lung cancers demonstrate loss of cellular signaling control pathways. EGFR-mutant non-small cell lung cancer cell lines constitutively express active ERK1/2 and require ERK activity for survival. DUSP4 is a negative regulator of ERK activity and is up-regulated in EGFR-mutant lung cancer cell lines relative to K-ras mutant cells. Both DUSP4 and family member, DUSP1, can bind ERK in vitro. However, only DUSP1 has detectable binding to ERK in vivo in cell lines of either genotype. Depletion of DUSP4 in EGFR-mutant cells unexpectedly results in loss of pERK whereas loss of DUSP4 in K-ras mutant cells predictably yields increased pERK. These data support a role for DUSP4, and perhaps DUSP1, as a positive activator of ERK in EGFR-mutant lung cancer cell lines independent of the ability to bind to ERK.
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PMID:Deregulation of DUSP activity in EGFR-mutant lung cancer cell lines contributes to sustained ERK1/2 signaling. 1983 51

Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants; it exhibits an anticancer effect on many malignancies. The most important chemotherapeutic agent for patients with advanced non-small cell lung cancer (NSCLC) is a platinum-containing compound such as cisplatin or carboplatin. The molecular mechanism underlying decreased NSCLC cell viability after treatment with emodin and cisplatin is unclear. Therefore, the aim of this study was to assess the cytotoxic effect of combined emodin and cisplatin on NSCLC cell lines and to clarify underlying molecular mechanisms. Exposure of human NSCLC cells to emodin decreased cisplatin-elicited ERK1/2 activation and ERCC1 protein induction by increasing instability of ERCC1 protein. Cisplatin alone did not affect expression of ERCC1 mRNA. However, emodin alone or combined with cisplatin significantly decreased expression of ERCC1 mRNA levels. Enhancement of ERK1/2 activation by transfection with constitutively active MKK1/2 (MKK1/2-CA) vector increased ERCC1 protein levels and protein stability, as well as increasing viability of NSCLC cells treated with emodin and cisplatin. In contrast, blocking ERK1/2 activation by U0126 (an MKK1/2 inhibitor) decreased cisplatin-elicited ERCC1 expression and enhanced cisplatin-induced cytotoxicity. Depletion of endogenous ERCC1 expression by si-ERCC1 RNA transfection significantly enhanced cisplatin's cytotoxic effect. In conclusion, ERCC1 protein protects NSCLC cells from synergistic cytotoxicity induced by emodin and platinum agents. Further investigation of combined emodin and cisplatin may lead to novel therapy in the future for NSCLC through down-regulating expression of ERCC1.
Lung Cancer 2010 Aug
PMID:Emodin enhances cisplatin-induced cytotoxicity via down-regulation of ERCC1 and inactivation of ERK1/2. 1996 80

Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It is a tyrosine kinase inhibitor and has anticancer effects on lung cancer. Rad51 plays a central role in homologous recombination, and high levels of Rad51 expression are observed in chemo- or radioresistant carcinomas. Our previous studies have shown that the mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 signal pathway maintains the expression of Rad51. Therefore, in this study, we hypothesized that emodin could enhance the effects of the antitumor antibiotic mitomycin C (MMC)-mediated cytotoxicity by decreasing the expression of Rad51 and the phosphorylation of ERK1/2. Exposure of the human non-small-cell lung cancer H1703 or A549 cell lines to emodin decreased the MMC-elicited phosphorylated ERK1/2 and Rad51 levels. Moreover, emodin significantly decreased the MMC-elicited Rad51 mRNA and protein levels by increasing the instability of Rad51 mRNA and protein. In emodin- and MMC-cotreated cells, ERK1/2 phosphorylation was enhanced by constitutively active MKK1/2 (MKK1/2-CA), thus increasing Rad51 protein levels and protein stability. The synergistic cytotoxic effects induced by emodin combined with MMC were remarkably decreased by MKK1-CA-mediated enhancement of ERK1/2 activation. Depletion of endogenous Rad51 expression by small interfering Rad51 RNA transfection significantly enhanced MMC-induced cell death and cell growth inhibition. In contrast, overexpression of Rad51 protects lung cancer cells from the synergistic cytotoxic effects induced by emodin and MMC. We conclude that suppression of Rad51 expression or a combination of emodin with chemotherapeutic agents may be considered as potential therapeutic modalities for lung cancer.
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PMID:Role of Rad51 down-regulation and extracellular signal-regulated kinases 1 and 2 inactivation in emodin and mitomycin C-induced synergistic cytotoxicity in human non-small-cell lung cancer cells. 2004 15

Attacking angiogenesis is considered an effective strategy for controls the expansion and metastasis of tumors and other related-diseases. The aim of this study was to assess the effects of moscatilin, a bibenzyl derivative, on VEGF and bFGF-induced angiogenesis in cultured human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. Moscatilin significantly inhibited growth of lung cancer cell line A549 (NSCLC) and suppressed growth factor-induced neovascularization. In addition, VEGF- and bFGF-induced cell proliferation, migration, and tube formation of HUVECs was markedly inhibited by moscatilin. Western blotting analysis of cell signaling molecules indicated that moscatilin inhibited ERK1/2, Akt, and eNOS signaling pathways in HUVECs. These results suggest that inhibition of angiogenesis by moscatilin may be a major mechanism in cancer therapy.
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PMID:Moscatilin, a bibenzyl derivative from the India orchid Dendrobrium loddigesii, suppresses tumor angiogenesis and growth in vitro and in vivo. 2005 28

YT-CB5, which had been continuously cultured with chrysotile B (CB)asbestos, showed impaired cytotoxicity with decreased expression of NKG2D and 2B4 NK cell-activating receptors. In the present study, the phosphorylation of extracellular signal-regulated kinase (ERK), which is known to induce degranulation downstream of many NK cell-activating receptors, was examined in YT-CB5 by flow cytometry and compared with the control line YT-Org. YT-CB5 exhibited impaired phosphorylation of ERK1/2 induced by the recognition of K562 cells, downstream of a process mediated by Src family kinase and phosphoinositide 3-kinase. YT-CB5 also exhibited impaired phosphorylation of ERK1/2 following incubation with K562 cells in the presence of anti-2B4 antibodies, where co-stimulation by 2B4 augmented the phosphorylation of ERK1/2 in YT-CB5 to a similar degree as in YT-Org. The phosphorylation of ERK1/2 induced by an inhibitor against phosphatase (PP) 1 and PP2A was also lower in YT-CB5 compared with YT-Org. Moreover, bead-bound antibodies to NKG2D, which contribute to cytotoxicity against K562 cells, induced negligible phosphorylation of ERK1/2 in YT-CB5, although antibodies to 2B4 induced a comparatively greater level of phosphorylation. Additionally, peripheral blood (PB-) NK cells with low expression of NKG2D showed lower phosphorylation of ERK1/2 mediated by anti-NKG2D antibodies compared with PB-NK cells with high expression of NKG2D. These results indicate that signal transduction events leading to the phosphorylation of ERK is impaired in YT-CB5 due to decreased expression of NKG2D. Further studies are required to clarify whether this suppressive effect of asbestos exposure on NK cells might promote lung cancer and mesothelioma in people who have inhaled asbestos.
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PMID:Decrease in phosphorylation of ERK following decreased expression of NK cell-activating receptors in human NK cell line exposed to asbestos. 2007 51

Bone is a frequent target of lung cancer metastasis, which is associated with significant morbidity and a dismal prognosis. This study analyzed the soluble factors secreted by lung cancer cells, which are responsible for increasing osteoclast differentiation. Addition of recombinant human interleukin-8 (rhIL-8), present in large amounts in A549-conditioned medium (CM) and NCI-H460-CM, mimicked the inductive effect of A549-CM and NCI-H460-CM on osteoclastogenesis. In contrast, depletion of interleukin-8 (IL-8) from A549-CM and NCI-H460-CM decreased the osteoclastogenesis-inductive properties of A549-CM and NCI-H460-CM. Induction of osteoclast differentiation by lung cancer-derived-CM and rhIL-8 was associated with increased phospholipase D (PLD) activation, and the activations of protein kinase C (PKC) alpha/betaII, extracellular signal-regulated kinase (ERK) 1/2 and AKT/the mammalian target of rapamycin (mTOR). Blocking PLD by a specific inhibitor significantly decreased osteoclast formation by inhibiting PKCs activation and subsequently attenuating the phosphorylation of ERK1/2. PLD inhibitor also completely decreased AKT and mTOR phosphorylation, whereas phosphatidylinositol-3-kinase (PI3K) inhibitor only partially decreased mTOR phosphorylation, suggesting that mTOR activation by PLD is through both PI3K/AKT-dependent and PI3K/AKT-independent manner. In addition, blocking AKT and ERK1/2 by a specific inhibitor also suppressed lung cancer-derived-CM and rhIL-8-induced osteoclast differentiation. Moreover, treatment of peripheral blood mononuclear cells with sera from invasive lung cancer patients increased the formation of osteoclasts. Our study suggests that IL-8 or IL-8-mediated PLD/PKC/ERK1/2 or PLD/AKT signaling is an attractive therapeutic target for osteolytic bone metastases in lung cancer patients.
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PMID:Phospholipase D signaling pathway is involved in lung cancer-derived IL-8 increased osteoclastogenesis. 2010 2

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90% of PDAC. Protein kinase Ciota (PKCiota) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCiota in pancreatic cancer. In this study, we evaluated the expression of PKCiota in human pancreatic cancer and the requirement for PKCiota for the transformed growth and tumorigenicity of PDAC cells. We find that PKCiota is significantly overexpressed in human pancreatic cancer, and high PKCiota expression correlates with poor patient survival. Inhibition of PKCiota expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCiota expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKCiota effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCiota-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCiota in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCiota in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCiota will be an effective target for pancreatic cancer therapy.
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PMID:Protein kinase Ciota is required for pancreatic cancer cell transformed growth and tumorigenesis. 2017 10

Iron regulatory proteins, IRP1 and IRP2, bind to mRNAs harboring iron responsive elements and control their expression. IRPs may also perform additional functions. Thus, IRP1 exhibited apparent tumor suppressor properties in a tumor xenograft model. Here we examined the effects of IRP2 in a similar setting. Human H1299 lung cancer cells or clones engineered for tetracycline-inducible expression of wild type IRP2, or the deletion mutant IRP2(Delta73) (lacking a specific insert of 73 amino acids), were injected subcutaneously into nude mice. The induction of IRP2 profoundly stimulated the growth of tumor xenografts, and this response was blunted by addition of tetracycline in the drinking water of the animals, to turnoff the IRP2 transgene. Interestingly, IRP2(Delta73) failed to promote tumor growth above control levels. As expected, xenografts expressing the IRP2 transgene exhibited high levels of transferrin receptor 1 (TfR1); however, the expression of other known IRP targets was not affected. Moreover, these xenografts manifested increased c-MYC levels and ERK1/2 phosphorylation. A microarray analysis identified distinct gene expression patterns between control and tumors containing IRP2 or IRP1 transgenes. By contrast, gene expression profiles of control and IRP2(Delta73)-related tumors were more similar, consistently with their growth phenotype. Collectively, these data demonstrate an apparent pro-oncogenic activity of IRP2 that depends on its specific 73 amino acids insert, and provide further evidence for a link between IRPs and cancer biology.
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PMID:Tumorigenic properties of iron regulatory protein 2 (IRP2) mediated by its specific 73-amino acids insert. 2040 6


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