| Inhibition of phosphatidylinositol 3-kinase/Akt signaling suppresses tumor cell proliferation and neuroendocrine marker expression in GI carcinoid tumors. | |
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MedLine Citation:
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PMID: 19588205 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Overactivation of PI3K/Akt signaling facilitates tumor proliferation in several cancers. We have shown that various signal transduction pathways promote tumorigenesis in carcinoid tumors, which exhibit endogenously high levels of active, phosphorylated Akt. Therefore, we hypothesized that inhibition of the PI3K/Akt pathway would suppress carcinoid tumor cell growth and neuroendocrine (NE) marker production. METHODS: Human carcinoid BON cells were treated in vitro with LY294002, a PI3-kinase inhibitor, or transfected with Akt1 siRNA. Tumor cell proliferation was measured by MTT for 6 days. The effect of LY294002 or Akt1 siRNA treatment was assessed by Western analysis. We examined the levels of phosphorylated Akt, total Akt, Akt1, and the NE markers human achaete-scute homolog1 (ASCL1) and chromogranin A (CgA). RESULTS: Treatment of BON cells with LY294002 reduced tumor cell proliferation (76%) in a dose-dependent manner. Growth also decreased in Akt1 siRNA transfected cells (26%). Levels of active, phosphorylated Akt and the NE tumor markers, ASCL1 and CgA, were diminished with both LY294002 and Akt1 siRNA treatments proportional to the degree of Akt inhibition. Total Akt, Akt2, and Akt3 levels were unaffected by these experiments. CONCLUSIONS: These data indicate that PI3K/Akt signaling performs a critical role in human carcinoid tumor cell survival and NE hormone generation. Furthermore, the development of novel therapeutics targeting Akt1 or components of the PI3K/Akt pathway may enhance the management of carcinoid disease. |
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Authors:
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Susan C Pitt; Herbert Chen; Muthusamy Kunnimalaiyaan |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-07-09 |
Journal Detail:
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Title: Annals of surgical oncology Volume: 16 ISSN: 1534-4681 ISO Abbreviation: Ann. Surg. Oncol. Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-09-25 Completed Date: 2009-12-15 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 9420840 Medline TA: Ann Surg Oncol Country: United States |
Other Details:
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Languages: eng Pagination: 2936-42 Citation Subset: IM |
Affiliation:
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Endocrine Surgery Research Laboratory, Department of Surgery, University of Wisconsin, Madison, WI, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Blotting, Western Carcinoid Tumor Cell Proliferation / drug effects* Chromogranin A / metabolism* Chromones / pharmacology* Gastrointestinal Neoplasms / drug therapy, metabolism, pathology* Humans Morpholines / pharmacology* Neuroendocrine Tumors / metabolism Phenotype Phosphatidylinositol 3-Kinases / antagonists & inhibitors*, metabolism Phosphorylation / drug effects Proto-Oncogene Proteins c-akt / antagonists & inhibitors*, genetics, metabolism RNA, Small Interfering / pharmacology Signal Transduction Tumor Cells, Cultured Tumor Markers, Biological / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA109053/CA/NCI NIH HHS; CA117117/CA/NCI NIH HHS; R01 CA109053-01A2/CA/NCI NIH HHS; R01 CA109053-02/CA/NCI NIH HHS; R01 CA109053-03/CA/NCI NIH HHS; R01 CA109053-04/CA/NCI NIH HHS; R01 CA109053-05/CA/NCI NIH HHS; R21 CA117117-01A2/CA/NCI NIH HHS; R21 CA117117-02/CA/NCI NIH HHS; T32 CA009614/CA/NCI NIH HHS; T32 CA009614-19/CA/NCI NIH HHS; T32 CA009614-20/CA/NCI NIH HHS; T32 CA009614-21/CA/NCI NIH HHS; T32 CA009614-22/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chromogranin A; 0/Chromones; 0/Morpholines; 0/RNA, Small Interfering; 0/Tumor Markers, Biological; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
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