Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All-trans retinoic acid (AR-t) is used for treating acute promyelocytic leukemia and renal cell carcinoma and it also has therapeutic value in several animal models of renal disease. Among its renal targets, mesangial cells have been widely studied: they have both retinoic acid receptors (RAR) and retinoid X receptors (RXR) and the cell growth is inhibited when human mesangial cells are incubated with 1-10 microM AR-t. Although his effect has been related with the antiproliferative action of AR-t, there are no studies on the involvement of apoptosis in AR-t induced cell growth when higher concentrations of retinoid are used. Our studies show that 25 microM AR-t triggers mesangial cell apoptosis assessed by light and fluorescence microscopy (Giemsa stain and acridine orange stain, respectively), DNA electrophoresis, flow cytometry (annexin-V) and immunocytochemistry (TUNEL). AR-t induced apoptosis was not inhibited by preincubation with the RXR pan-antagonist HX531 nor with the RAR pan-antagonist AGN 193109, this suggesting RAR and RXIR are not involved in AR-t induced cell death. Previous results of our group showed that ERK (extracellular regulated kinase) and INK (c-Jun kinase), two members of the MAP (mitogen activated protein) kinase family, are involved in non apoptotic effects of AR-t on mesangial cells. Therefore we focussed on the stress activated p38 kinase, the third member of the MAPK family, to investigate its involvement in AR-t induced apoptosis. The results confirmed a role of p38 since: 1) preincubation with B5203589, a p38 inhibitor, inhibited ARA induced apoptosis; 2) incubation with AR-t induced p38 phosphorilation after few minutes and p38 remained phosphorilated for at least 8 hours and 3) AR-t induced p38 phosphorilation was inhibited by SB203589. These data suggest that AR-t might have toxic side effects on the kidney but also suggest that AR-t could be an useful inhibitor of pathological mesangial cell expansion.
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PMID:[All-trans retinoic acid induces apoptosis in human mesangial cells: involvement of stress activated p38 kinase]. 1591 49

Following treatment with a demethylating agent, 5 of 11 renal cell carcinoma (RCC) cell lines showed increased expression of hepatocyte growth factor (HGF) activator inhibitor type 2 (HAI-2/SPINT2/Bikunin), a Kunitz-type protease inhibitor that regulates HGF activity. As activating mutations in the MET proto-oncogene (the HGF receptor) cause familial RCC, we investigated whether HAI-2/SPINT2 might act as a RCC tumor suppressor gene. We found that transcriptional silencing of HAI-2 in RCC cell lines was associated with promoter region methylation and HAI-2/SPINT2 protein expression was down-regulated in 30% of sporadic RCC. Furthermore, methylation-specific PCR analysis revealed promoter region methylation in 30% (19 of 64) of clear cell RCC and 40% (15 of 38) of papillary RCC, whereas mutation analysis (in 39 RCC cell lines and primary tumors) revealed a missense substitution (P111S) in one RCC cell line. Restoration of HAI-2/SPINT2 expression in a RCC cell line reduced in vitro colony formation, but the P111S mutant had no significant effect. Increased cell motility associated with HAI-2/SPINT2 inactivation was abrogated by treatment with extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phospholipase C-gamma inhibitors, but not by an inhibitor of atypical protein kinase C. These findings are consistent with frequent epigenetic inactivation of HAI-2/SPINT2, causing loss of RCC tumor suppressor activity and implicate abnormalities of the MET pathway in clear cell and papillary sporadic RCC. This information provides opportunities to develop novel targeted approaches to the treatment of RCC.
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PMID:Tumor suppressor activity and epigenetic inactivation of hepatocyte growth factor activator inhibitor type 2/SPINT2 in papillary and clear cell renal cell carcinoma. 1593 Feb 77

Chromophobe renal cell carcinoma (RCC) and collecting duct carcinoma (CDC) are derived from the collecting duct epithelia, although their morphology, molecular biologic characteristics and clinical behaviors are quite different. Herein is presented a case of RCC possessing the chromophobe RCC and CDC elements occurring in a 64 year-old Japanese woman. The patient was referred to Yokohama City University Hospital with complaints of persistent back pain and fever. Radiologic examinations revealed a left renal tumor, and radical nephrectomy was performed. The patient died with multiple metastases, 8 months after the operation. The resected tumor showed an invasive growth, and its cut surface was heterogenous with hemorrhage and necrosis. Histologically, the tumor was composed of chromophobe elements with dedifferentiation, and CDC elements. The chromophobe and CDC elements had obvious histological transition. Lectin histochemistry and immunohistochemistry confirmed that this tumor was derived from the distal nephron. c-KIT, p53 and Ki67 antigen showed differential localization between the chromophobe and CDC elements, even in the transitional areas. Along with the previous reports, the present case seemed to be composite RCC derived from the collecting duct, which might present clues to elucidate carcinogenesis in the distal nephron.
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PMID:Composite distal nephron-derived renal cell carcinoma with chromophobe and collecting duct carcinomatous elements. 1594 94

Inactivating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are associated with clear cell renal cell carcinoma (VHL-/- RCC), the most frequent malignancy of the human kidney. The VHL protein targets the alpha subunits of hypoxia-inducible factor (HIF) transcription factor for ubiquitination and degradation. VHL-/- RCC cells fail to degrade HIF resulting in the constitutive activation of its target genes, a process that is required for tumorigenesis. We recently reported that HIF activates the transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) pathway in VHL-defective RCC cells. Here, we show that short hairpin RNA (shRNA)-mediated inhibition of EGFR is sufficient to abolish HIF-dependent tumorigenesis in multiple VHL-/- RCC cell lines. The 2alpha form of HIF (HIF-2alpha), but not HIF-1alpha, drives in vitro and in vivo tumorigenesis of VHL-/- RCC cells by specifically activating the TGF-alpha/EGFR pathway. Transient incubation of VHL-/- RCC cell lines with small interfering RNA directed against EGFR prevents autonomous growth in two-dimensional culture as well as the ability of these cells to form dense spheroids in a three-dimensional in vitro tumor assay. Stable expression of shRNA against EGFR does not alter characteristics associated with VHL loss including constitutive production of HIF targets and defects in fibronectin deposition. In spite of this, silencing of EGFR efficiently abolishes in vivo tumor growth of VHL loss RCC cells. These data identify EGFR as a critical determinant of HIF-2alpha-dependent tumorigenesis and show at the molecular level that EGFR remains a credible target for therapeutic strategies against VHL-/- renal carcinoma.
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PMID:Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL-/- renal cancer. 1595 67

Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are both important for tumour progression in renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-VEGF antibody demonstrate a delay in the time to disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of VEGF, FLT3, KIT and platelet-derived growth factor receptor tyrosine kinases, such as sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with sorafenib, an inhibitor of multiple tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the mammalian target of rapamycin. Conversely, EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of hypoxia-inducible factor-1alpha, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted therapy could lead to a new standard of care for RCC.
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PMID:Targeted therapy in renal cell carcinoma. 1618 67

To study the effect of Trastuzumab in combination with IFN alpha-2b on HER2 and MRP1 of ACHN in vitro, ACHN cell line of RCC was cultured by employing cell culture. The tetrazolium-based colorimetric assay was used to evaluate the growth-inhibiting effect of Trastuzumab with IFN alpha-2b. SP method was utilized to determine the expression of HER2 and MRP1 of the cells. Our results showed that Trastuzumab had inhibitory effect on the growth of renal tumor cells and reversing effect on the multi-drug-resistance (MDR) in RCC in a time- and dose-dependent manner. Treated with Trastuzumab with or without IFN alpha-2b, the expression of HER2 and MRP1 genes of RCC was decreased significantly (P<0.05). It was concluded that Trastuzumab with IFN alpha-2b could inhibit the proliferation of RCC and the expression of HER2 and MRP1 of ACHN and to some extent, reverse the MDR of the tumor cells.
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PMID:Effect of trastuzumab in combination with IFN alpha-2b on HER2 and- MRP1 of ACHN. 1620 Dec 86

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, the elucidation of the molecular mechanisms underlying RCC development has led to the identification of promising targets for novel therapeutic agents. The involvement of the Von Hippel-Lindau protein pathway in clear cell RCC suggests that downstream targets of this pathway, namely, signaling through vascular endothelial growth factor (VEGF) in endothelial cells, platelet-derived growth factor (PDGF) in endothelial cells and pericytes, and the epidermal growth factor receptor (EGFR) pathway in tumor cells are all reasonable and rational therapeutic targets. A number of agents are in development that target VEGF (bevacizumab, a recombinant, humanized monoclonal antibody) or its receptor, VEGFR (PTK787, SU011248, and BAY 43-9006, all of which are small molecule inhibitors). Agents targeting EGFR also are being investigated clinically (gefitinib, cetuximab, erlotinib, and ABX-EGF). The Raf/MEK/ERK pathway is an important downstream convergence point for signaling through VEGFR, platelet-derived growth factor receptor (PDGFR), and EGFR (all have receptor tyrosine kinase activity) and also has important antiapoptotic effects, thereby providing an attractive target for intervention. In addition to inhibiting VEGFR and PDGFR-mediated angiogenic pathways, BAY 43-9006 has been shown to inhibit the Raf/MEK/ERK pathway at the level of Raf kinase. MEK-directed therapeutic approaches are also in development. Given that multiple molecular pathways are implicated in tumor cell growth, antitumor activity may be increased by using individual agents that target multiple pathways, or by combining different agents to allow vertical or horizontal inhibition of relevant pathways.
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PMID:Targeted agents for the treatment of advanced renal cell carcinoma. 1624 Apr 52

Renal cell carcinoma (RCC) is a highly treatment-resistant tumor type; however, advances in elucidating the molecular pathophysiology underlying RCC has led to the identification of promising targets for therapeutic intervention. In clear-cell RCC, mutations to the von Hippel-Lindau (VHL) gene results in the up regulation of many proteins necessary for tumor growth and survival--such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and platelet derived growth factor (PDGF), which are involved in tumor-initiated angiogenesis. Carbonic anhydrase IX and signaling via the epidermal growth factor receptor (EGFR) are involved in tumor cell proliferation and are also up regulated by mutation in the VHL gene. The intracellular messenger pathways phosphoinositide 3-kinase (PI3K) and Raf/MEK/ERK act as convergence points for positive growth signaling; the Raf/MEK/ERK pathway is also implicated in apoptosis. Several agents in development target VEGF (bevacizumab), the VEGF receptor (PTK787, SU11248, VEGF-trap, and BAY 43-9006), the PDGF receptor (SU11248 and BAY 43-9006), or the EGF receptor (gefitinib, cetuximab, ABX-EGF, and erlotinib). The intracellular Raf/MEK/ERK signaling cascade has been targeted at either the level of Raf (BAY 43-9006, ISIS 5132) or MEK (CI-1040, PD184352 and ARRY-142886), and PI3K signaling is disrupted by CCI-779. WX-G250 targets the G250 antigen, and PS-341 disrupts the 26S proteasome mediating the degradation of intracellular proteins. Given that multiple pathways contribute to tumor growth, anti-tumor activity may be increased by agents targeting multiple pathways, or by combining agents to allow horizontal or vertical inhibition of multiple pathways.
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PMID:Targeted agents for the treatment of advanced renal cell carcinoma. 1630 62

Clear-cell renal cell carcinoma (RCC) is characterized by the loss of von Hippel-Lindau disease protein and the resultant dysregulation of the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), platelet-derived growth factor-beta (PDGF-beta)/PDGF receptor-beta (PDGFR-beta), and transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGFR)/Raf pathways, which contribute to angiogenesis, lymphangiogenesis, and tumor cell growth and survival. Significant advances in the treatment of clear-cell RCC have been derived from agents that target these pathways, including the multiple-kinase inhibitors (MKIs) sorafenib, sunitinib, and AG013736, which target multiple VEGFRs as well as PDGFR-beta. Sorafenib has the added advantage of inhibiting multiple different Raf isoforms, which enables it to target TGF-alpha/EGFR signaling and may also enhance its inhibition of VEGFR and PDGFR-beta. This review will examine the recent advances in our understanding of the biology of clear-cell RCC and show how those advances have helped delineate new targets of opportunity for treatment. It will also present the early clinical results of agents that target the pathways dysregulated in clear-cell RCC, with special emphasis on sorafenib and the other active MKIs, and will describe the scientific rationales for ongoing and future sorafenib-based combination therapy trials in RCC.
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PMID:Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. 1642 82

The conventional form of renal cell carcinoma (RCC) is a highly vascular tumour with an extremely poor prognosis in the presence of metastases. Significant progress has recently been made in the understanding of the molecular mechanisms leading to the vascular phenotype of renal cancer In particular, VHL disease constitutes a useful study model, as inactivation of the VHL gene leads to accumulation of HIF factor, inducing activation of genes such as: VEGF, PDGF, EPO, CaIX and TGF-alpha. The fact that VHL inactivation has been found in about 70% of sporadic renal cancers constitutes the best rationale to target the products of these genes. Candidate drugs currently target VEGF, VEGFR, PDGFR and tyrosine kinase receptors, which are necessary for intracellular signal transduction. The preliminary results of phase II trials in metastatic renal cancer, usually as second-line therapy, are very encouraging. The results of phase III trials will soon be available, but many studies are already evaluating these drugs either as first-line or in combination. Urologists have an opportunity to become familiar with these drugs by actively participating in trials of adjuvant therapy that will be initiated in the near future.
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PMID:[Molecular pathways of tumour angiogenesis and new targeted therapeutic approaches in renal cancer]. 1673 53


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