Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Capecitabine (Xeloda) is a prodrug of 5-FU used in the clinical management of advanced breast cancer. It is metabolized first in the liver by carboxylesterases to generate 5'-deoxy-5-flurocytidine ribose (5'-DFCR), which is subsequently converted to 5'-deoxy-5-fluorouridine ribose (5'-DFUR) by cytidine deaminase in tumour and normal tissues. The conversion of 5'-DFUR to the cytotoxic 5-FU, occurs primarily in the tumour and is catalyzed by thymidine phosphorylase (TP). Prior work in head and neck cancer showed that cell treatment with an inhibitor of the epidermal growth receptor (EGFR) gefitinib led to an increase in TP expression and sensitized them to 5'-DFUR. This work seeks to investigate the factors influencing the potency of gefitinib + 5'-DFUR combination. Here, we studied these factors in a panel of six human breast cancer cell lines, with varied levels of sensitivity to gefitinib. Our results first confirmed that 5'-DFUR potency linearly correlates with TP basal levels in the panel of cell lines. In contrast, the strength of the synergistic effect of the gefitinib + 5'-DFUR combination, as measured by their combination indices (CI) correlates with pEGFR percent inhibition and with the modulation of TP expression by gefitinib (as quantitated by TP fold change) rather than TP basal levels. The results, in toto, suggest that the extent of modulation of TP by gefitinib may be used as a predictor of tumour sensitivity to gefitinib + capecitabine/5'-DFUR combinations.
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PMID:Inhibition of EGFR phosphorylation in a panel of human breast cancer cells correlates with synergistic interactions between gefitinib and 5'-DFUR, the bioactive metabolite of Xeloda. 2191 35

Carcinogen-induced oral cavity squamous cell carcinoma (OSCC) incurs significant morbidity and mortality and constitutes a global health challenge. To gain further insight into this disease, we generated cell line models from 7,12-dimethylbenz(a)anthracene-induced murine primary OSCC capable of tumor formation upon transplantation into immunocompetent wild-type mice. Whereas several cell lines grew rapidly and were capable of metastasis, some grew slowly and did not metastasize. Aggressively growing cell lines displayed ERK1/2 activation, which stimulated expression of CD44, a marker associated with epithelial to mesenchymal transition and putative cancer stem cells. MEK (MAP/ERK kinase) inhibition upstream of ERK1/2 decreased CD44 expression and promoter activity and reduced cell migration and invasion. Conversely, MEK1 activation enhanced CD44 expression and promoter activity, whereas CD44 attenuation reduced in vitro migration and in vivo tumor formation. Extending these findings to freshly resected human OSCC, we confirmed a strict relationship between ERK1/2 phosphorylation and CD44 expression. In summary, our findings identify CD44 as a critical target of ERK1/2 in promoting tumor aggressiveness and offer a preclinical proof-of-concept to target this pathway as a strategy to treat head and neck cancer.
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PMID:ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. 2208 49

Activity of heparanase is implicated strongly in dissemination of metastatic tumor cells and cells of the immune system. In addition, heparanase enhances the phosphorylation of selected signaling molecules, including SRC and EGFR, in a manner that requires secretion but not enzymatic activity of heparanase and is mediated by its C-terminal domain. Clinically, heparanase staining is associated with larger tumors and increased EGFR phosphorylation in head and neck carcinoma. We hypothesized that signal transducer and activator of transcription (STAT) proteins mediate the protumorigenic function of heparanase downstream of the EGFR. We provide evidence that heparanase enhances the phosphorylation of STAT3 and STAT5b but not STAT5a. Moreover, enhanced proliferation of heparanase transfected cells was attenuated by STAT3 and STAT5b siRNA, but not STAT5a or STAT1 siRNA. Clinically, STAT3 phosphorylation was associated with head and neck cancer progression, EGFR phosphorylation, and heparanase expression and cellular localization. Notably, cytoplasmic rather than nuclear phospho-STAT3 correlated with increased tumor size (T-stage; p = 0.007), number of metastatic neck lymph nodes (p = 0.05), and reduced survival of patients (p = 0.04).
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PMID:Heparanase induces signal transducer and activator of transcription (STAT) protein phosphorylation: preclinical and clinical significance in head and neck cancer. 2219

Head and neck squamous cell carcinoma is now the 8th most common cancer affecting men in the United States largely due to a rising epidemic of oropharynx cancer (tonsil and tongue base) associated with the human papillomavirus (HPV). The median overall survival for recurrent or metastatic head and neck cancer (R/M HNSCC) remains less than 1 year despite modern chemotherapy and targeted agents. Palliative chemotherapy and the epidermal growth factor receptor inhibitor, cetuximab, constitute the backbone of treatment for patients with R/M HNSCC. Platinum doublets studied in phase III trials include cisplatin/5-FU, cisplatin/paclitaxel, and cisplatin/pemetrexed. Platinum chemotherapy in combination with 5-fluorouracil and cetuximab has resulted in the longest median overall survival. Combination platinum regimens increase response rates and toxicity but not survival and should be reserved for patients who are symptomatic from their disease for whom the benefit of a partial response may be worth the cost of increased treatment-related side effects. For many patients who are asymptomatic with a low disease burden, single agent regimens are appropriate to balance treatment with side effects. Drugs commonly used as single agents in the treatment of R/M HNSCC include docetaxel, paclitaxel, cetuximab, capecitabine, pemetrexed, and methotrexate. Best supportive care alone is often appropriate for poor performance status patients. Palliative radiation therapy is beneficial for treating symptomatic metastatic sites. Aggressive symptom management is imperative for all patients and often should include referral to experts in palliative care and pain management. New therapies currently under investigation include mTOR inhibitors, anti-angiogenic agents, and IGF1R inhibitors. Given the poor prognosis for most patients with R/M HNSCC, enrollment in clinical trials investigating novel approaches to therapy should be encouraged.
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PMID:Current treatment options for metastatic head and neck cancer. 2225 84

Patients with serosal (pleural or peritoneal) spread of malignancy have few definitive treatment options and consequently have a very poor prognosis. We have previously shown that photodynamic therapy (PDT) can be an effective treatment for these patients, but that the therapeutic index is relatively narrow. Here, we test the hypothesis that EGFR and STAT3 activation increase survival following PDT, and that inhibiting these pathways leads to increased PDT-mediated direct cellular cytotoxicity by examining BPD-PDT in OvCa and NSCLC cells. We found that BPD-mediated PDT stimulated EGFR tyrosine phosphorylation and nuclear translocation, and that EGFR inhibition by erlotinib resulted in reduction of PDT-mediated EGFR activation and nuclear translocation. Nuclear translocation and PDT-mediated activation of EGFR were also observed in response to BPD-mediated PDT in multiple cell lines, including OvCa, NSCLC and head and neck cancer cells, and was observed to occur in response to porfimer sodium-mediated PDT. In addition, we found that PDT stimulates nuclear translocation of STAT3 and STAT3/EGFR association and that inhibiting STAT3 signaling prior to PDT leads to increased PDT cytotoxicity. Finally, we found that inhibition of EGFR signaling leads to increased PDT cytotoxicity through a mechanism that involves increased apoptotic cell death. Taken together, these results demonstrate that PDT stimulates the nuclear accumulation of both EGFR and STAT3 and that targeting these survival pathways is a potentially promising strategy that could be adapted for clinical trials of PDT for patients with serosal spread of malignancy.
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PMID:Photodynamic therapy activated signaling from epidermal growth factor receptor and STAT3: Targeting survival pathways to increase PDT efficacy in ovarian and lung cancer. 2298 30

With the exploration of new horizons in the frontiers of genetic linkage with head and neck cancer by advanced molecular biological technique it may be possible to know the various steps involved in the cancer development and new prognostic markers for not only predicting prognosis but also progression and predisposition including routine diagnostic tests for mutantgenes for a better diagnosis and treatment of squamous cell cancers of head and neck. Various oncogens and their products so far identified are ras, myc, c-erb, Bl, PRAD-.l, int-2, hst-1 and p 53 etc with lirikage to head and neck malignancy. The HLA gene association is the most convincing evidence for the role of genetics in the aetiology of nasopharyngeal cancer. EGFR looks to be a promising prognostic indicator as its interaction with the polypeptide epidermal growth factor stimulates proliferation of target cells.
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PMID:Oncogens in ENT and head and neck - a review. 2311 52

Lin28 is a developmentally regulated RNA binding protein which has recently emerged as key regulator in the biogenesis of the let-7 micro-RNA family. While the expression of Lin28b has been linked to advanced tumor stage, the precise molecular mechanism(s) by which Lin28b drives disease progression is still being unraveled. Herein, we generated a let-7-resistant Lin28b ORF, stably expressed in the FaDu head and neck cancer (HNC) cell line. FaDu-Lin28b cells exhibited enhanced tumor growth in vitro and in vivo. Global gene and micro-RNA expression analyses revealed significant enrichment in several pathways involved in cell migration, chromatin remodeling, and cellular stress response. Direct regulation of selected genes (HMGA2, CCND2, IGF1R, and IGF2BP2) via a let-7-Lin28b mechanism was validated. Notably, up-regulation of several genes in the IGF pathway in Lin28b-expressing cells was observed. Functional studies revealed significant increase in the survival of Lin28b-expressing cells when cultured under stress conditions, which was dependent on the presence of IGF1. Therefore, our data identified several novel gene targets for Lin28b-let7, and revealed a novel mechanism by which Lin28b promote tumorigenesis. Concordantly, clinical examinations of Lin28b, IGF2BP2 and IGF2 revealed a significant association between the expression of these genes with disease relapse, thereby corroborating the potential relevance for the Lin28b/IGF axis in HNC progression.
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PMID:Lin28b promotes head and neck cancer progression via modulation of the insulin-like growth factor survival pathway. 2348 25

EGFR overexpression and chromosome 3p deletion are two frequent events in head and neck cancers. We previously mapped the smallest region of recurrent copy-number loss at 3p12.2-p14.1. LRIG1, a negative regulator of EGFR, was found at 3p14, and its copy-number loss correlated with poor clinical outcome. Inducible expression of LRIG1 in head and neck cancer TW01 cells, a line with low LRIG1 levels, suppressed cell proliferation in vitro and tumor growth in vivo. Gene expression profiling, quantitative RT-PCR, chromatin immunoprecipitation, and western blot analysis demonstrated that LRIG1 modulated extracellular matrix (ECM) remodeling and EGFR-MAPK-SPHK1 transduction pathway by suppressing expression of EGFR ligands/activators, MMPs and SPHK1. In addition, LRIG1 induction triggered cell morphology changes and integrin inactivation, which coupled with reduced SNAI2 expression. By contrast, knockdown of endogenous LRIG1 in TW06 cells, a line with normal LRIG1 levels, significantly enhanced cell proliferation, migration and invasiveness. Such tumor-promoting effects could be abolished by specific MAPK or SPHK1 inhibitors. Our data suggest LRIG1 as a tumor suppressor for head and neck cancers; LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers.
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PMID:LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling. 2362 15

Matrix metalloproteinases (MMPs) are over-expressed in nearly all cancers. To study novel regulatory factors of MMP expression in head and neck cancer (HNC), we screened a total of 636 candidate genes encoding putative human transmembrane proteins using MMP promoter reporter in a dual luciferase assay system. Three genes GPR65, AXL and TNFRSF10B dramatically activated the induction of MMP3 expression. The induction of MMP expression by GPR65 was further confirmed in A549 and/or FaDu cells. GPR65 mediated MMP induction under acidic conditions. The AP-1 binding site in MMP3 promoter was crucial for MMP3 induction. Moreover, the A549 cells infected by recombinant adenovirus of GPR65 showed accelerated cell invasion. In conclusion, we validate that GPR65 is vital regulatory genes upstream of MMP3, and define a novel mechanism of MMP3 regulation by proton-sensing G-protein-coupled receptors.
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PMID:Identification of GPR65, a novel regulator of matrix metalloproteinases using high through-put screening. 2370 9

Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys).
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PMID:Novel targets in HPV-negative head and neck cancer: overcoming resistance to EGFR inhibition. 2381 96


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