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

Even though lung cancer patients harboring a mutation in the epidermal growth factor receptor (EGFR) gene exhibit an initial dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs), acquired resistance is almost inevitable after a progression-free period of approximately 10 months. A secondary point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) is a molecular mechanism that produces a drug-resistant variant of the targeted kinase. The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs. Nevertheless, several lines of evidence indicate that the T790M mutation confers growth advantage to cancer cells, and it was shown that mice expressing tetracycline-inducible EGFR transgenes harboring the T790M mutation develop lung tumors. Thus, T790M mutation seems to play a double role in the survival of lung cancer cells. Several second-generation EGFR-TKIs are currently being developed to overcome the acquired resistance caused by the T790M mutation. MET (met proto-oncogene) amplification or activation of IGF1R are reported as alternative mechanisms for acquired resistance to EGFR-TKIs. Clarification of the pathways leading to acquired resistance is essential to maximize the efficacy of EGFR-TKI therapy for patients with lung cancer.
 ...
PMID:EGFR T790M mutation: a double role in lung cancer cell survival? 1909 99

Phosphorylation of proteins on serine or threonine residues preceding proline is a major regulatory mechanism in cell proliferation and transformation, which is catalyzed specifically by Pin1, a peptidylprolyl isomerase. Pin1 is overexpressed in several human cancers. The expression of Pin1 mRNA in the circulation was assessed in 26 patients with non-small-cell lung cancer who underwent surgical resection. They were randomly assigned to a pulmonary artery first ligation group and a pulmonary vein first ligation group. Pin1 mRNA expression in blood samples from patients with lung cancer, controls with benign lung disease, and healthy subjects were determined by a real-time reverse transcriptase polymerase chain reaction. Compared to those with benign lung disease and healthy controls, Pin1 mRNA was overexpressed in patients with non-small-cell lung cancer, and the levels correlated with lymph node-positive disease and tumor stage. Expression of Pin1 mRNA in the distal part of the pulmonary vein was significantly higher than in the proximal part. Postoperative Pin1 mRNA expression was significant lower than preoperative expression. There was no significant difference in Pin1 expression between groups based on pulmonary vessel ligation. These findings suggest that Pin1 might be a useful tumor marker for cancer therapy.
 ...
PMID:Expression of Pin1 mRNA in non-small-cell lung cancer patients. 1959 46

Lung cancer remains a leading cause of disease globally, with smoking being the largest single cause. Phase I enzymes, including cytochrome P(450), family 1, subfamily A, polypeptide 1 (CYP1A1), are involved in the activation of carcinogens, such as polycyclic aromatic hydrocarbons, to reactive intermediates that are capable of binding covalently to DNA to form DNA adducts, potentially initiating the carcinogenic process. The aim of the present study was to investigate the association of CYP1A1 gene polymorphisms and haplotypes with lung cancer risk. A case-control study was carried out on 1,040 nonsmall cell lung cancer (NSCLC) cases and 784 controls to investigate three CYP1A1 variants, CYP1A1*2A (rs4646903; thymidine to cytosine substitution at nucleotide 3801 (3801T>C)), CYP1A1*2C (rs1048943; 2455A>G; substitution of isoleucine 462 with valine (exon 7)) and CYP1A1*4 (rs1799814; 2453C>A; substitution of threonine 461 with asparagine (exon 7)) using PCR restriction fragment length polymorphism methods. The CYP1A1*2A and CYP1A1*2C variants were significantly over-represented in NSCLC cases compared with controls, whereas the CYP1A1*4 variant was under-represented. CYP1A1 haplotypes (in allele order CYP1A1*4, CYP1A1*2C, CYP1A1*2A) CGC and CGT were associated with an increased risk of lung cancer, whereas AAT was associated with decreased lung cancer risk in this population. The present study has identified risk haplotypes for CYP1A1 in NSCLC and confirmed that CYP1A1 polymorphisms are a minor risk factor for NSCLC.
 ...
PMID:Genetic association study of CYP1A1 polymorphisms identifies risk haplotypes in nonsmall cell lung cancer. 1960 85

Matrix metalloproteinase-1 (MMP-1) is an inflammation-inducible neutral protease that mediates extracellular matrix remodeling and promotes tumor invasion. In this study, we examined the activation of MMP-1 gene expression in A549 lung carcinoma cells stimulated with the inflammatory cytokine interleukin-1beta (IL-1beta). We found that MMP-1 mRNA levels were maximal following 16 hours of IL-1beta stimulation and that this correlated with the expression of the transcription factor CCAAT enhancer-binding protein-beta (CEBPB). Knockdown of CEBPB expression with short hairpin RNA abrogated the expression of MMP-1, MMP-3, and MMP-10 in IL-1beta-stimulated A549 cells. An established CEBP element in the MMP-1 promoter was found to be required for basal and IL-1beta-induced transcription. Electrophoresis mobility shift assays showed that CEBPB binds to this promoter element maximally 16 hours after IL-1beta stimulation. DNA affinity chromatography studies showed that the LAP1, LAP2, and LIP isoforms of CEBPB bind to the IL-1beta-responsive CEBPB site in the MMP-1 promoter. Exogenous expression of the LAP1 and LAP2 isoforms stimulated the MMP-1 promoter, whereas LIP had no effect. Phosphorylation of CEBPB at Thr(235) peaked at 16 hours in IL-1beta-stimulated cells. The MEK inhibitor U0126 inhibited this phosphorylation and reduced MMP-1 gene induction. These studies establish CEBPB as an important mediator of metalloproteinase gene activation during inflammatory responses in lung cancer cells and highlight the different regulatory roles of CEBPB isoforms.
 ...
PMID:CCAAT enhancer binding protein-beta regulates matrix metalloproteinase-1 expression in interleukin-1beta-stimulated A549 lung carcinoma cells. 1972 73

Arsenic trioxide (As(2)O(3)) has been established to be an effective agent for treating acute promyleocytic leukemia. Laboratory data suggest that As(2)O(3) induces apoptosis of several solid tumor cells including lung cancer cells. Regions of tissue hypoxia often arise in aggressive solid tumors, and hypoxic tumors exhibit augmented invasiveness and metastatic ability in several malignancies. Furthermore, hypoxia may impair the treatment efficiency; therefore, we studied the cytotoxic effect of As(2)O(3) on human lung adenocarcinoma cell lines A549 and A549/R (resistant to vincristine, adriamycin and mitomycin etc.) grown under normoxic and hypoxic (1% oxygen) conditions. At both normoxia and hypoxia, 5, 10 and 15 microM As(2)O(3) induced evident growth inhibition and apoptosis in A549 cells as well as A549/R cells after 48 hours of exposure. In contrast, the conventional chemotherapeutic drug vincristine showed lowered efficiency in hypoxic A549 cells. As(2)O(3) induced G(2)/M cell cycle arrest in both normoxic and hypoxic A549 cells. As(2)O(3) significantly decreased the messenger RNA (mRNA) levels of Cyclin B(1) and survivin and the protein levels of Cyclin B(1), phospho-CDC(2) (Thr 161) and survivin in both normoxic and hypoxic A549 cells. Together, our findings indicated that As(2)O(3) significantly inhibited the proliferation of lung cancer cells via G(2)/M cell cycle arrest and induction of apoptosis at both normoxia and hypoxia, and the induction of apoptosis was associated with down regulation of survivin.
 ...
PMID:Arsenic trioxide inhibits the growth of human lung cancer cell lines via cell cycle arrest and induction of apoptosis at both normoxia and hypoxia. 1982 57

Pin1 specifically catalyzes the cis/trans isomerization of phospho-Ser/Thr-Pro bonds and plays an important role in many cellular events through the effects of conformational change on the function of its biological substrates, including cell division cycle 25 C (Cdc25C), c-Jun and p53. Pin1 is overexpressed in many human cancer tissues, including breast, prostate and lung cancer. Its expression correlates with cyclin D1 levels, which contribute to cell transformation. Overexpression of Pin1 promotes tumor growth, while inhibition of Pin1 causes tumor cell apoptosis. Pin1 plays an important role in oncogenesis and therefore may serve as an effective anticancer target. Many inhibitors of Pin1 have been discovered, including several classes of designed inhibitors (alkene isosteres, reduced amides, indanyl ketones) and natural products (juglone, pepticinnamin E analogues, PiB and its derivatives obtained from a library screen). Pin1 inhibitors could be used as a novel type of anticancer drug by blocking cell cycle progression. Therefore, Pin1 represents a new diagnostic and therapeutic anticancer drug target.
 ...
PMID:Pin1 as an anticancer drug target. 1989 Apr 97

Lung cancer remains the most common cause of death for malignancy in both men and women. Current therapies for NSCLC patients are inefficient due to the lack of diagnostic and therapeutic markers. The phospho-Ser/Thr-Pro specific prolyl-isomerase Pin1 is overexpressed in many different cancers, including NSCLC, and may possibly be used as a target for cancer therapy. We identified 79 cases with the follow-up survival and investigated the clinical relevance of Pin1 expression in NSCLC patients. To validate the oncogenic potential of Pin1 in lung cells, we overexpressed Pin1 in Glc82 cells, and downregulated Pin1 by RNA interference in H1299 cells. The 5-year survival rate of the 79 patients was 54.6%. High expression of Pin1 correlated with poor survival by univariate analysis as well as by multivariate analysis, demonstrating that high expression of Pin1 was an independent prognostic factor. Consistent with the clinical findings, overexpression of Pin1 in Glc82 cells increased cell growth and colony formation and tumorigenicity in nude mice including cell migration, invasion. To further validate the role of Pin1 in lung cancer carcinogenesis, lentivirus-mediated siRNA targeting of Pin1 resulted in the stable suppression of both cell growth, anchorage-independent growth in soft agar and tumorigenic including cell migration, invasion in H1299 cells. Pin1 expression may be an unfavorable prognostic factor in patients of NSCLC patients, and these results indicate that Pin1 may have a role in tumor development and metastasis and thus could serve as a novel target for treatment of NSCLC.
 ...
PMID:Pin1 expression contributes to lung cancer: Prognosis and carcinogenesis. 2002 88

Capsaicin, a natural product of the Capsicum species of red peppers, is known to induce apoptosis and suppress growth. Non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a cytokine associated with pro-apoptotic and antitumorigenic property in colorectal and lung cancer. Our data demonstrate that capsaicin leads to induction of apoptosis and up-regulates NAG-1 gene expression at the transcriptional level. Overexpression of CCAAT/enhancer binding protein beta (C/EBPbeta) caused a significant increase of basal and capsaicin-induced NAG-1 promoter activity. We subsequently identified C/EBPbeta binding sites in the NAG-1 promoter responsible for capsaicin-induced NAG-1 transactivation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed binding of C/EBPbeta to the NAG-1 promoter. Capsaicin treatment resulted in an increase of phosphorylated serine/threonine residues on C/EBPbeta, and the immunoprecipitation study showed that capsaicin enhanced binding of C/EBPbeta with glycogen synthase kinase 3beta (GSK3beta) and activating transcription factor 3 (ATF3). The phosphorylation and interaction of C/EBPbeta with GSK3beta and ATF3 are decreased by the inhibition of the GSK3beta and Protein Kinase C pathways. Knockdown of C/EBPbeta, GSK3beta or ATF3 ameliorates NAG-1 expression induced by capsaicin treatment. These data indicate that C/EBPbeta phosphorylation through GSK3beta may mediate capsaicin-induced expression of NAG-1 and apoptosis through cooperation with ATF3 in human colorectal cancer cells.
 ...
PMID:NSAID-activated gene-1 as a molecular target for capsaicin-induced apoptosis through a novel molecular mechanism involving GSK3beta, C/EBPbeta and ATF3. 2011 Feb 83

The cyclic-AMP response element-binding protein (CREB) is a nuclear transcription factor activated by phosphorylation at Ser133 by multiple serine/threonine (Ser/Thr) kinases. Upon phosphorylation, CREB binds the transcriptional co-activator, CBP (CREB-binding protein), to initiate CREB-dependent gene transcription. CREB is a critical regulator of cell differentiation, proliferation and survival in the nervous system. Recent studies have shown that CREB is involved tumor initiation, progression and metastasis, supporting its role as a proto-oncogene. Overexpression and over-activation of CREB were observed in cancer tissues from patients with prostate cancer, breast cancer, non-small-cell lung cancer and acute leukemia while down-regulation of CREB in several distinct cancer cell lines resulted in inhibition of cell proliferation and induction of apoptosis, suggesting that CREB may be a promising target for cancer therapy. Although CREB, as a transcription factor, is a challenging target for small molecules, various small molecules have been discovered to inhibit CREB phosphorylation, CREB-DNA, or CREB-CBP interaction. These results suggest that CREB is a suitable transcription factor for drug targeting and therefore targeting CREB could represent a novel strategy for cancer therapy.
 ...
PMID:Targeting CREB for cancer therapy: friend or foe. 2037 Jun 81

The epidermal growth factor receptor (EGFR) plays an important role in cancer by activating downstream signals important in growth and survival. Inhibitors of EGFR are frequently selected as treatment for cancer including lung cancer. We performed an unbiased and comprehensive search for EGFR phosphorylation events related to somatic activating mutations and EGFR inhibitor (erlotinib) sensitivity. EGFR immunoprecipitation combined with high resolution liquid chromatography-mass spectrometry and label free quantitation characterized EGFR phosphorylation. Thirty (30) phosphorylation sites were identified including 12 tyrosine (pY), 12 serine (pS), and 6 threonine (pT). Site-specific phosphorylation was monitored by comparing ion signals from the corresponding unmodified peptide. Phosphorylation sites related to activating mutations in EGFR as well as sensitivity to erlotinib were identified using 31 lung cancer cell lines. We identified three sites (pY1092, pY1110, pY1172) correlated with activating mutations and three sites (pY1110, pY1172, pY1197) correlated with erlotinib sensitivity. Five sites (pT693, pY1092, pY1110, pY1172, and pY1197) were inhibited by erlotinib in concentration-dependent manner. Erlotinib sensitivity was confirmed using liquid chromatography coupled to multiple reaction monitoring (LC-MRM) and quantitative Western blotting. This LC-MS/MS strategy can quantitatively assess site-specific EGFR phosphorylation and can identify relationships between somatic mutations or drug sensitivity and protein phosphorylation.
 ...
PMID:Mass spectrometry mapping of epidermal growth factor receptor phosphorylation related to oncogenic mutations and tyrosine kinase inhibitor sensitivity. 2108 Jun 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>