| Transient potential receptor channel 4 controls thrombospondin-1 secretion and angiogenesis in renal cell carcinoma. | |
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MedLine Citation:
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PMID: 18021253 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Angiogenic switch in renal cell carcinoma (RCC) is attributed to the inactivation of the von Hippel-Lindau tumor suppressor, stabilization of hypoxia inducible factor-1 transcription factor and increased vascular endothelial growth factor. To evaluate the role of an angiogenesis inhibitor, thrombopsondin-1 (TSP1), we compared TSP1 production in human RCC and normal tissue and secretion by the normal renal epithelium (human normal kidney, HNK) and RCC cells. Normal and RCC tissues stained positive for TSP1, and the levels of TSP1 mRNA and total protein were similar in RCC and HNK cells. However, HNK cells secreted high TSP1, which rendered them nonangiogenic, whereas RCC cells secreted little TSP1 and were angiogenic. Western blot and immunostaining revealed TSP1 in the cytoplasm of RCC cells on serum withdrawal, whereas, in HNK cells, it was rapidly exported. Seeking mechanisms of defective TSP1 secretion, we discovered impaired calcium uptake by RCC in response to vascular endothelial growth factor. In HNK cells, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, a calcium chelator, simulated TSP1 retention, mimicking the RCC phenotype. Further analysis revealed a profound decrease in transient receptor potential canonical ion channel 4 (TRPC4) Ca(2+) channel expression in RCC cells. TRPC4 silencing in HNK cells caused TSP1 retention and impaired secretion. Double labeling of the secretory system components revealed TSP1 colocalization with coatomer protein II (COPII) anterograde vesicles in HNK cells. In contrast, in RCC cells, TSP1 colocalized with COPI vesicles, pointing to the retrograde transport to the endoplasmic reticulum caused by misfolding. Our study indicates that TRPC4 loss in RCC leads to impaired Ca(2+) intake, misfolding, retrograde transport and diminished secretion of antiangiogenic TSP1, thus enabling angiogenic switch during RCC progression. |
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Authors:
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Dorina Veliceasa; Marina Ivanovic; Frank Thilo-Schulze Hoepfner; Praveen Thumbikat; Olga V Volpert; Norm D Smith |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-11-15 |
Journal Detail:
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Title: The FEBS journal Volume: 274 ISSN: 1742-464X ISO Abbreviation: FEBS J. Publication Date: 2007 Dec |
Date Detail:
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Created Date: 2007-12-13 Completed Date: 2008-03-27 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101229646 Medline TA: FEBS J Country: England |
Other Details:
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Languages: eng Pagination: 6365-77 Citation Subset: IM |
Affiliation:
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Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western COP-Coated Vesicles / drug effects, metabolism Calcium / metabolism, pharmacokinetics Carcinoma, Renal Cell / blood supply*, pathology Cell Line Cell Line, Tumor Cell Proliferation Chelating Agents / pharmacology Corneal Neovascularization / genetics, metabolism, pathology Egtazic Acid / analogs & derivatives, pharmacology Female Fluorescent Antibody Technique Humans Immunohistochemistry Kidney Neoplasms / blood supply*, pathology Mice Mice, Inbred C57BL Neovascularization, Pathologic / genetics, metabolism, pathology* Rats Rats, Inbred F344 Reverse Transcriptase Polymerase Chain Reaction TRPC Cation Channels / genetics, metabolism Thrombospondin 1 / genetics, metabolism*, secretion Transfection |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL077471/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chelating Agents; 0/TRPC Cation Channels; 0/TRPC4 ion channel; 0/Thrombospondin 1; 139890-68-9/1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; 67-42-5/Egtazic Acid; 7440-70-2/Calcium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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