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)

Gefitinib (Iressa, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor that can block growth factor-mediated cell proliferation and extracellular signal-regulated kinases 1/2 (ERK1/2) activation. High-level Rad51 expression has been reported in chemoresistant or radioresistant carcinomas. In this study, we examined the role of Rad51 in regulating the response to gefitinib among different human lung cancer cell lines. The H520 line (human squamous cell carcinoma) was less sensitive to gefitinib compared with the H1650 (human adenocarcinoma) or A549 (human bronchioloalveolar carcinoma) lines. In H1650 and A549 cells but not in H520 cells, gefitinib decreased cellular levels of phospho-ERK1/2 and Rad51 protein and message levels. Moreover, gefitinib decreased Rad51 protein levels by enhancing Rad51 protein instability through 26S proteasome-mediated degradation. Inhibition of endogenous Rad51 levels by si-Rad51 RNA transfection significantly enhanced gefitinib-induced cytotoxicity. In contrast, transfection with constitutively active MKK1 vector could restore both Rad51 protein levels and cell survival inhibited by gefitinib. The MKK1/2-ERK1/2 signaling pathway constitutes the upstream signaling for maintaining Rad51 message and protein levels. Rad51 protein can protect lung cancer cells from cytotoxic effects induced by gefitinib. Suppression of Rad51 may be a novel lung cancer therapeutic modality to overcome drug resistance to gefitinib.
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PMID:Role of repair protein Rad51 in regulating the response to gefitinib in human non-small cell lung cancer cells. 1900 45

EGFR (ErbB1) and ErbB2 receptors stimulate several intracellular signaling pathways in non-small-cell lung cancer (NSCLC). Adenocarcinomas (AC) and squamous cell carcinomas (SCC) are NSCLC subtypes with distinct clinico-pathological features, and responses to ErbB-targeted inhibitors treatment. To evaluate the causes of these differences, tissue microarrays with samples from NSCLC patients (189 AC and 56 SCC) were used to study EGFR and ErbB2 expression and phospho-activation of ERK1/2, AKT, STAT3 and SRC ErbB-mediators by immunohistochemistry and Western blot, and EGFR and ErbB2 gene amplification by FISH. EGFR expression was higher in SCC than in AC (P<0.001), while ErbB2 showed similar low levels. Phosphorylated (p) ERK, pAKT, pSTAT3 and pSRC levels were prevalent in AC (P< or =0.002). EGFR levels and signaling mediators activation were differentially associated with each of the pathologies. Whereas in AC the expression and amplification of EGFR were linked to AKT activation (P< or =0.050), in SCC its expression was correlated with pSTAT3 (P=0.024). In addition, pSTAT3 was correlated with pERK and pAKT only in AC (P< or =0.045). Biomarker levels were also differentially associated with the clinico-pathologic variables. In AC, EGFR and pSRC increasing scores correlated with female sex and the smoking habit (P< or =0.008), while ErbB2 amplification increased with advanced age and tumor stage (P< or =0.047), and pERK1/2 and pSTAT3 levels correlated with early tumor stage (P< or =0.045). In SCC, EGFR amplification was stronger in younger patients (P=0.013), pERK1/2 in the older ones (P=0.050), and pSTAT3 amplification was stronger in women (P=0.001). These data support that AC and SCC lung tumors are distinct entities at the molecular level, and that their signaling status in combination with their clinico-pathologic variables may be considered for differential targeted therapies.
Lung Cancer 2009 Jul
PMID:Differential ErbB receptor expression and intracellular signaling activity in lung adenocarcinomas and squamous cell carcinomas. 1904 92

Celecoxib (Celebrex) is a cyclooxygenase-2 (COX-2) selective inhibitor and gefitinib (Iressa(R), ZD1839) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for human non-small cell lung cancer (NSCLC). The addition of celecoxib to gefitinib to prolong the survival of patients with NSCLC still remains controversial and needs to be investigated. The Rad51 protein is essential for homologous recombination repair, and is overexpressed in chemo- or radioresistant carcinomas. In this study, we characterize the role of celecoxib in the cytotoxicity, ERK1/2 activation and Rad51 expression affected by gefitinib in NSCLC cells. We show that celecoxib can enhance the cytotoxicity induced by gefitinib in NSCLC cells. Treatment with celecoxib alone has no effect on the ERK1/2 activation, Rad51 mRNA and protein levels, however, combined treatment with gefitinib results in a significant reduction of phospho-ERK1/2 and Rad51 protein levels, and triggers the degradation of Rad51 via a 26S proteasome-dependent pathway. Expression of constitutively active MKK1/2 vectors (MKK1/2-CA) significantly rescues the decreased ERK1/2 activity, and restores Rad51 protein levels and cell survival under co-treatment with gefitinib and celecoxib. Furthermore, blocking ERK1/2 activation by U0126 (MKK1/2 inhibitor) and knocking down Rad51 expression by transfection with small interfering RNA of Rad51 can enhance the cytotoxicity of celecoxib.
Lung Cancer 2009 Sep
PMID:The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells. 1915 34

Studies have suggested that retinoids prevent lung cancer by interacting with nuclear retinoid receptors. However, clinical trials with beta-carotene increased lung cancer mortality. We recently showed that beta-carotene stimulates the proliferation of small airway-derived adenocarcinoma by increasing cAMP signaling. Here, we have tested the hypothesis that beta-carotene may stimulate squamous cell carcinoma cells via similar mechanisms. We determined the effects of beta-carotene in cell lines from squamous cell carcinomas and large airway epithelia on proliferation by MTT assays in the presence and absence of inhibitors. Signaling via cAMP/PKA was measured by immunoassays and PKA activation assay. Phosphorylated ERK1/2 was determined by Western blotting. beta-carotene significantly inhibited proliferation and phosphorylation of ERK1/2 by Galphas-mediated signaling involving adenylyl cyclase, cAMP, PKA and ERK1/2. These findings introduce a non-genomic inhibitory mechanism of beta-carotene and emphasize the need for the development of marker-guided lung cancer prevention.
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PMID:Non-genomic inhibitory signaling of beta-carotene in squamous cell carcinoma of the lungs. 1928 67

LKB1 encodes a serine/threonine kinase generally inactivated in human lung cancers, which mediates cancer cell proliferation, migration and differentiation, but its biological function has not been completely elucidated. In this study, we demonstrated that LKB1 was associated with a substantial reduction of c-myc expression by using an inducible LKB1 expression system in the LKB1-null lung cell line A549. Nevertheless, the reduction of the c-Myc gene expression was not accompanied by corresponding reduction of mRNAs but protein, which can be abrogated by a proteosome inhibitor (MG132), suggesting that the reduction was associated with their increased degradation rather than transcriptional controls. Our results implied that the expression of c-Myc protein decreased by LKB1 in transfected cells may be a contributory factor in the process of cell proliferation. Overexpression of the LKB1 gene could inhibit the activation of ERK1/2 and STAT3 signaling pathways involved in the cell proliferation. Thus, LKB1-induced functional operation on c-Myc in promoting cell proliferation may occur in a novel mechanism, which may be regulated by ERK1/2 and/or STAT3 signal pathways in human lung carcinoma cells. Furthermore, our results give some insights into the understanding of how LKB1 inactivation contributes to lung carcinogenesis and emphasizes the central role played by LKB1 in lung cancer development.
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PMID:Overexpression of the LKB1 gene inhibits lung carcinoma cell proliferation partly through degradation of c-myc protein. 1928 90

Hypoxia, a common phenomenon in human solid tumors, is associated with invasion and metastasis in various tumors. Hypoxia inducible factors (HIFs) are key molecules in the hypoxic response, and regulate the activation of specific genes, which mediate many of the adaptations to hypoxia. CC chemokine receptor 7 (CCR7) has been shown to play a critical role in cell chemotaxis and homing, which are key steps in cancer metastasis. A study has demonstrated that hypoxia could upregulate CCR7 in breast cancer cells. The CCR7 gene presents hypoxia response element (HRE; (A)/(G)CGTG). We presumed that hypoxia induced upregulation of HIFs promoted the expression of CCR7 facilitating tumor cells invasion and metastasis. In this study, we firstly examined the relationship of CCR7 and HIF-1alpha, HIF-2alpha in 94 cases non-small cell lung cancer (NSCLC) tissues by immunohistochemistry. The results showed that CCR7 expression correlated positively with HIF-1alpha and HIF-2alpha, all of them correlated with clinical stage and lymph node metastasis. Then, we investigated whether hypoxia induce the expression of CCR7 through HIF-1alpha and/or HIF-2alpha and observed the effects of upregulated CCR7 on the migration and invasion of lung cancer cells. We found that hypoxia induced HIF-1alpha and HIF-2alpha expression, which upregulated CCR7 expression; inhibiting HIF-1alpha or HIF-2alpha expression in BE1 and A549 cells by RNAi led to the decrease of CCR7 expression, inhibition of migratory and invasive abilities, and the effects of HIF-1alpha were more significant. Moreover, the migration and invasion of BE1 cells were increased as well as the expression of p-ERK1/2 after CCR7 transfection, but the cells invasive ability was inhibited after blocking p-ERK1/2 with PD98059 and CCR7 with specific antibody. In summary, our study demonstrated that hypoxia-HIF-1alpha, 2alpha-CCR7-ERK1/2 pathway could regulate the migration and invasion of lung cancer cells under hypoxic conditions and promote metastasis of lung cancer.
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PMID:Hypoxia induced CCR7 expression via HIF-1alpha and HIF-2alpha correlates with migration and invasion in lung cancer cells. 1930 50

The p53-dependent RR small subunit (p53R2) protein, a newly identified member of the ribonucleotide reductase family, plays a key role in the p53-dependent cellular response to DNA. Several recent studies have suggested that p53R2 also plays an important role in suppressing the invasive potential of human cancer cells. However, the cellular mechanism that regulates invasiveness remains largely unknown. In this study, we show that p53R2 interacts with MEK2 (extracellular signal-regulated kinase (ERK) kinase 2-mitogen-activated protein kinase (MAPK) kinase 2), the molecule immediately upstream of ERK in the Ras-Raf-MAPK signaling cascade. In co-immunoprecipitation and immunofluorescence analyses, we found that p53R2 and MEK2 interact physically in cultured mammalian cells, and that the p53R2 segment comprising amino acids 161-206 is critical for this interaction. Moreover, serum-induced phosphorylation of MEK1/2 and ERK1/2 was greatly augmented in human cancer cells expressing small-interfering RNA against p53R2. On the other hand, phosphorylation of MEK1/2 and ERK1/2 in human cancer cells was markedly attenuated by overexpression of p53R2. Furthermore, MEK2 was required for p53R2 knockdown-induced enhancement of the invasive ability and anchorage-independent growth of human lung cancer H1299 cells. Taken together, these findings show that p53R2 negatively modulates serum-induced MEK-ERK activity and inhibits the MEK-ERK-mediated malignancy potential of human cancer cells.
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PMID:Ribonucleotide reductase small subunit p53R2 suppresses MEK-ERK activity by binding to ERK kinase 2. 1939 49

Emodin, a tyrosine kinase inhibitor, is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It reportedly exhibits an anticancer effect on lung cancer. Gefitinib (Iressa) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for human non-small cell lung cancer (NSCLC). However, the molecular mechanism of how emodin combined with gefitinib decreases NSCLC cell viability is unclear. The recombinase protein Rad51 is essential for homologous recombination repair, and Rad51 overexpression is resistant to DNA double-strand break-inducing cancer therapies. In this study, we found that emodin enhanced the cytotoxicity induced by gefitinib in two NSCLC cells lines, A549 and H1650. Emodin at low doses of 2-10 microM did not affect ERK1/2 activation, mRNA, and Rad51 protein levels; however, it enhanced a gefitinib-induced decrease in phospho-ERK1/2 and Rad51 protein levels by enhancing Rad51 protein instability. Expression of constitutively active MKK1/2 vectors (MKK1/2-CA) significantly rescued the reduced phospho-ERK1/2 and Rad51 protein levels as well as cell viability on gefitinib and emodin cotreatment. Blocking of ERK1/2 activation by U0126 (an MKK1/2 inhibitor) lowered Rad51 protein levels and cell viability in emodin-treated H1650 and A549 cells. Knockdown of Rad51 expression by transfection with si-Rad51 RNA enhanced emodin cytotoxicity. In contrast, Rad51 overexpression protected the cells from the cytotoxic effects induced by emodin and gefitinib. Consequently, emodin-gefitinib cotreatment may serve as the basis for a novel and better therapeutic modality in the management of advanced lung cancer.
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PMID:Emodin enhances gefitinib-induced cytotoxicity via Rad51 downregulation and ERK1/2 inactivation. 1950 57

Thioredoxin (TRX) is a key component of redox regulation and has been indicated to play an essential role in cell survival and growth. Here, we investigated the molecular mechanism of TRX in the regulation of cell survival and growth by using RNA interference (RNAi) in A549 lung cancer and MCF7 breast cancer cells. TRX knockdown did not significantly increase the basal level of cell death without exposure to stress, but CDDP-induced cell death was enhanced. Meanwhile, TRX knockdown resulted in significant cell-cycle arrest at the G(1) phase. Cyclin D1 expression was reduced by TRX knockdown at the protein and mRNA levels. TRX knockdown caused suppression of activation of the cyclin D1 promoter through elements including AP-1. TRX knockdown also reduced the levels of phosphorylated ERK1/2 and the nuclear translocation of ERK 1/2 induced by EGF. These results suggest that TRX is an important regulator of the cell cycle in the G(1) phase via cyclin D1 transcription and the ERK/AP-1 signaling pathways.
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PMID:Thioredoxin regulates cell cycle via the ERK1/2-cyclin D1 pathway. 1962 16

This study investigates the anticancer effect of dehydrocostuslactone (DHE), a medicinal plant-derived sesquiterpene lactone, on human non-small cell lung cancer cell lines, A549, NCI-H460 and NCI-H520. Our results show that DHE inhibits the proliferation of A549, NCI-H460 and NCI-H520 cells. DHE-induced apoptosis in both A549 and NCI-H460 cells. DHE triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels, PKR-like ER kinase (PERK) phosphorylation, inositol requiring protein 1 (IRE1) and CHOP/GADD153 upregulation, X-box transcription factor-1 (XBP-1) mRNA splicing, and caspase-4 activation. The release of calcium triggered the production of ROS, which further enhances calcium overloading and subsequently activates p38, JNK and ERK1/2. Both IRE1 miRNA transfection and BAPTA-AM pretreatment inhibit DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death through ER stress. Importantly, a novel anticancer agent for the treatment of non-small cell lung cancer, and is supported by animal studies which have shown a dramatic 50% reduction in tumor size after 28 days of treatment. This study demonstrates that DHE may be a novel anticancer agent for the treatment of non-small cell lung cancer.
Lung Cancer 2010 Jun
PMID:Oxidative and endoplasmic reticulum stress signaling are involved in dehydrocostuslactone-mediated apoptosis in human non-small cell lung cancer cells. 1970 Feb 17


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