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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The heavy burden of lung cancer, which includes the highest worldwide mortality of any cancer, and its resistance to standard approaches (smoking cessation, screening, and therapy), have motivated an intense interest in chemoprevention of this disease. Randomized controlled trials of agents (including retinoids, beta-carotene, and vitamin E) to prevent lung cancer have produced only disappointing clinical results to date. New, molecular-targeted approaches are advancing rapidly, however, with many promising targets and interactive signaling pathways for developing novel agents and combinatorial approaches in this setting. This promise is illustrated by recent studies of 15-hydroxyprostaglandin dehydrogenase, which plays a critical role in polyunsaturated fatty acid metabolism and (like another important target, prostacyclin) is downstream of cyclooxygenase-2. 15-hydroxyprostaglandin dehydrogenase degrades prostaglandin E(2), appears to have tumor suppressor activity, and can be induced both by peroxisome proliferator-activated receptor-gamma ligands and an epidermal growth factor receptor inhibitor. Other important targets/pathways include the insulin-like growth factor axis, phosphoinositide 3-kinase pathway, cyclin D and E family members, and epigenetic events. Defining highest lung cancer risk (eg, establishing molecular risk models through long-term analyses of high-risk cohorts) will facilitate the clinical development of molecular-targeted prevention that will potentially reduce the enormous burden of lung cancer.
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PMID:Advances in the biology of lung cancer chemoprevention. 1588 5

Gene expression profile analysis of non-small cell lung cancers (NSCLC) and subsequent functional analyses revealed that human ANLN, a homologue of anillin, an actin-binding protein in Drosophila, was transactivated in lung cancer cells and seemed to play a significant role in pulmonary carcinogenesis. Induction of small interfering RNAs against ANLN in NSCLC cells suppressed its expression and resulted in growth suppression; moreover, treatment with small interfering RNA yielded cells with larger morphology and multiple nuclei, which subsequently died. On the other hand, induction of exogenous expression of ANLN enhanced the migrating ability of mammalian cells by interacting with RHOA, a small guanosine triphosphatase, and inducing actin stress fibers. Interestingly, inhibition of phosphoinositide 3-kinase/AKT activity in NSCLC cells decreased the stability of ANLN and caused a reduction of the nuclear ANLN level. Immunohistochemical staining of nuclear ANLN on lung cancer tissue microarrays was associated with the poor survival of NSCLC patients, indicating that this molecule might serve as a prognostic indicator. Our data imply that up-regulation of ANLN is a common feature of the carcinogenetic process in lung tissue, and suggests that selective suppression of ANLN could be a promising approach for developing a new strategy to treat lung cancers.
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PMID:ANLN plays a critical role in human lung carcinogenesis through the activation of RHOA and by involvement in the phosphoinositide 3-kinase/AKT pathway. 1635 38

Bone morphogenetic protein-2 (BMP-2) is an evolutionary conserved protein that is essential for embryonic development. BMP-2 is highly expressed in approximately 98% of human lung carcinomas with little expression in normal lung tissues. BMP-2 has been shown to enhance mobility, invasiveness, and metastasis of cancer cell lines. During development, BMP-2 induces the proto-oncogene phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway to regulate stem cell differentiation. We show that BMP-2 induces the phosphorylation of mTOR in A549 and H1299 lung cancer cell lines, which is attenuated by the PI3K antagonists LY-294002 and wortmannin. p70S6 kinase, which is a direct downstream target of mTOR, is also regulated by BMP-2 in lung cancer cell lines. We find that BMP-2 induces cyclin E in A549 and H1299 cells, which is mediated by the PI3K/mTOR signaling pathway. The regulation of cyclin E by BMP-2 occurs through a Smad 1/5-independent mechanism. Forced expression of BMP-2 in A549 cells (A549/BMP-2) induces transformation as shown by an increase in foci formation. The mTOR antagonist, rapamycin, prevented foci formation of the A549/BMP-2 cells. This study provides evidence that BMP-2-mediated transformation of lung cancer cells involves the activation of the PI3K/mTOR signaling pathway.
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PMID:Bone morphogenetic protein-2-induced transformation involves the activation of mammalian target of rapamycin. 1638 May 5

The small molecular inhibitor MK886 is known to block 5-lipoxygenase-activating protein ALOX5AP and shows antitumor activity in multiple human cell lines. The broad antitumor therapeutic window reported in vivo for MK886 in rodents supports further consideration of this structural class. Better understanding of the mode of action of the drug is important for application in humans to take place. Affymetrix microarray study was conducted to explore MK886 pharmacologic mechanism. Ingenuity Pathway Analysis software was applied to validate the results at the transcriptional level by putting them in the context of an experimental proteomic network. Genes most affected by MK886 included actin B and focal adhesion components. A subsequent National Cancer Institute-60 panel study, RT-PCR validation followed by confocal microscopy, and Western blotting also pointed to actin B down-regulation, filamentous actin loss, and disorganization of the transcription machinery. In agreement with these observations, MK886 was found to enhance the effect of UV radiation in H720 lung cancer cell line. In light of the modification of cytoskeleton and cell motility by lipid phosphoinositide 3-kinase products, MK886 interaction with actin B might be biologically important. The low toxicity of MK886 in vivo was modeled and explained by binding and transport by dietary lipids. The rate of lipid absorbance is generally higher for tumors, suggesting a promise of a targeted liposome-based delivery system for this drug. These results suggest a novel antitumor pharmacologic mechanism.
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PMID:Ingenuity network-assisted transcription profiling: Identification of a new pharmacologic mechanism for MK886. 1655 67

Small cell lung cancer (SCLC) is an aggressive form of lung cancer, which represents 13% of all cases and is strongly associated with cigarette smoking. The survival of SCLC patients is dismal and has not greatly improved in the last 20 years, despite advances in chemotherapy regimens and a better understanding of SCLC biology. The development of resistance to chemotherapy and metastasis are commonly recognized as important causes of poor clinical outcome in SCLC. Targeting receptor tyrosine kinase (RTK) signalling represents an attractive approach to develop new drugs for SCLC, in view of the accumulating data demonstrating that polypeptide growth factors play a key role in driving SCLC cell proliferation, chemoresistance and metastasis. The insulin-like growth factor-I receptor (IGF-IR), c-Kit, vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) have been identified as potential drug targets in SCLC. Moreover, downstream signalling mediators of RTKs, such as phosphoinositide 3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) may also represent attractive candidate molecules for anti-cancer therapies in SCLC. Here we will review the available data concerning results with RTK inhibitors in SCLC and the clinical trials undertaken to investigate the potential of these compounds as anti-tumour agents in SCLC.
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PMID:Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far? 1736 33

Lung cancer is the leading cause of cancer-related mortality in the world, with more than 1 million deaths per year. Over the past years, lung cancer treatment has been based on cytotoxic agents and an improvement in the outcome and quality of life for patients has been observed. However, it has become clear that additional therapeutic strategies are urgently required in order to provide an improved survival benefit for patients. Two major intracellular signaling pathways, the Ras/Raf/extracellular signal-regulated kinase (Erk) and the phosphoinositide 3-kinase (PI3K)/Akt pathways have been extensively studied in neoplasia, including lung cancer. Furthermore, the study of constitutively activated receptor tyrosine kinases (RTKs) and their downstream signaling mediators has opened a promising new field of investigation for lung cancer treatment. Since both the Ras/Raf/Erk and the PI3K/Akt pathways are downstream of a plethora of activated RTKs, they have been extensively studied for the development of novel anti-tumor agents. Moreover, the mammalian target of rapamycin (mTOR) has been identified as a downstream target of the PI3K/Akt pathway. Rapamycin and its derivatives are highly selective and very potent inhibitors of mTOR and initial pre-clinical and clinical studies have reported encouraging results for different tumor types. Nevertheless for lung cancer, this approach has not been successful yet. Here we will review the molecular basis of PI3K/Akt/mTOR signaling in lung cancer and further discuss the therapeutic potential of multi-targeted strategies involving mTOR inhibitors.
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PMID:Targeting mTOR signaling in lung cancer. 1754 May 77

The mechanisms by which tobacco promotes lung cancer remain incompletely understood. Herein, we report that nicotine, a major component of tobacco, promotes the proliferation of cultured non-small cell lung carcinoma (NSCLC) cells; this effect was most noticeable at 5 days. However, nicotine had no effect on apoptosis of NSCLC cells. In experiments designed to unveil the mechanisms for this effect, we found that nicotine also stimulated mRNA and protein expression of fibronectin. Fibronectin is a matrix glycoprotein that regulates important cellular processes (e.g., adhesion, proliferation, and differentiation) and is highly expressed in tobacco-related lung disorders. Of note, reagents against the integrin alpha5beta1 (antibodies, RGD peptides, alpha5 shRNA) blocked the mitogenic effects of nicotine. Thus, nicotine stimulated NSCLC cell proliferation indirectly via fibronectin induction. We then focused on the mechanisms responsible for nicotine-induced fibronectin expression in NSCLC cells and found that nicotine stimulated the surface expression of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), and that alpha-bungarotoxin, an inhibitor of alpha7 nAChR, abolished the nicotine-induced fibronectin response. The fibronectin-inducing effects of nicotine were associated with activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signaling pathways, and were abrogated by inhibitors of ERK (PD98059), PI3-K (LY294002), and mTOR (rapamycin), but not by inhibitors of protein kinase (PK)C (calphostin C) and PKA (H89). These observations suggest that nicotine stimulates NSCLC proliferation through induction of fibronectin, and that these events are mediated through nAChR-mediated signals that include ERK and PI3-K/mTOR pathways. This work highlights the role of fibronectin and alpha5beta1 integrins as potential targets for anti-lung cancer therapies.
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PMID:Nicotine stimulates human lung cancer cell growth by inducing fibronectin expression. 1760 Mar 15

Epithelial-to-mesenchymal transition (EMT) is a fundamental biological process whereby epithelial cells lose their polarity and undergo a transition to a mesenchymal phenotype. When cancer cells invade adjacent tissues, they use a mechanism akin to EMT, and understanding the molecular mechanisms that drive this transition will facilitate studies into new targets for prevention of metastasis. Extracellular stimuli, such as growth factors, and their cytosolic effectors cooperate to promote EMT. In highly fibrotic cancers like lung cancer, it is thought that extracellular matrix molecules, including collagen, can initiate signals that promote EMT. Here, we present data showing that collagen I induces EMT in non-small cell lung cancer cell lines, which is prevented by blocking transforming growth factor (TGF)-beta3 signaling. In addition, we show that collagen I-induced EMT is prevented by inhibitors of phosphoinositide 3-kinase and extracellular signal-related kinase signaling, which promotes transcription of TGF-beta3 mRNA in these cells. Thus, our data are consistent with the hypothesis that collagen I induces EMT in lung cancer cells by activating autocrine TGF-beta3 signaling. Epidermal growth factor also seems to initiate EMT via a TGF-dependent mechanism.
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PMID:Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. 1767 89

Inhibition of one or more members of the phosphoinositide 3-kinase (PI3K) family for the treatment of respiratory diseases remains the goal of many pharmaceutical companies over the past 20 years. Here we briefly review the PI3K family, then focus on the assessment of each isoform as a drug discovery target. The rationale for PI3Kalpha inhibition in the treatment of lung cancer, and PI3Kbeta inhibitors in pulmonary thrombotic processes, are balanced with a potential side effect profile affecting metabolism and/or foetal development. Roles for PI3Kdelta in inflammatory lung diseases and PI3Kgamma in asthma are weighed against the consequences of manipulating key immune cell populations. We also discuss the current status and future potential of PI3K inhibitors in respiratory disease.
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PMID:Inhibition of PI-3 kinase for treating respiratory disease: good idea or bad idea? 1839 61

Cisplatin is widely used for the treatment of solid tumors, including small cell lung cancers, but its success is often compromised due to relapse and resistance to further treatment. p70 ribosomal S6 kinase (p70S6K) has been shown to be upregulated in lung cancer cells. In the present study, we investigated whether the p70S6K pathway contributes to cisplatin resistance in human small cell lung cancer H69 cells. The levels of phosphorylated p70S6K and its downstream target S6 but not total p70S6K or S6 were elevated in the H69 cells that acquired resistance to cisplatin (H69/CP) compared to parental H69 cells. Cisplatin treatment resulted in the activation of p70S6K and downregulation of p70S6K was associated with cisplatin-induced PARP cleavage. While the ability of cisplatin to induce apoptosis was attenuated in H69/CP cells, inhibition of p70S6K by rapamycin enhanced cisplatin-induced apoptosis in these cells as evident by the increase in cisplatin-induced poly(ADP-ribose) polymerase (PARP) cleavage. The phosphoinositide 3-kinase (PI3K) inhibitor Ly294002 alone induced PARP cleavage and further augmented cisplatin-induced PARP cleavage. In contrast, inhibition of extracellular signal-regulated kinase (ERK) by U0126 attenuated cisplatin-induced PARP cleavage. Both rapamycin and Ly294002 enhanced cisplatin-induced acti-vation of ERK1/2. Taken together, these results suggest that activation of p70S6K contributes to cisplatin resistance in small cell lung cancer H69 cells, and inhibition/downregulation of p70S6K as well as activation of ERK1/2 could circumvent cisplatin resistance.
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PMID:Constitutive activation of p70 S6 kinase is associated with intrinsic resistance to cisplatin. 1842 42


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