| Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin. | |
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MedLine Citation:
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PMID: 19706758 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We investigated the genotype-dependent therapeutic potential of targeting the phosphoinositide 3-kinase (PI3K)/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine, whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations, whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time shows that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies. |
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Authors:
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Dingxie Liu; Peng Hou; Zhi Liu; Guojun Wu; Mingzhao Xing |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-08-25 |
Journal Detail:
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Title: Cancer research Volume: 69 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-09-16 Completed Date: 2009-10-07 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 7311-9 Citation Subset: IM |
Affiliation:
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Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Growth Processes / drug effects Cell Line, Tumor Humans Mice Mice, Nude Oncogene Protein v-akt / antagonists & inhibitors, genetics*, metabolism Phosphatidylinositol 3-Kinases / antagonists & inhibitors, biosynthesis, genetics*, metabolism Phosphorylcholine / analogs & derivatives*, pharmacology Protein Kinases / metabolism* RNA, Small Interfering / genetics Signal Transduction / genetics Sirolimus / analogs & derivatives*, pharmacology TOR Serine-Threonine Kinases Thyroid Neoplasms / drug therapy*, enzymology*, genetics, pathology Transfection Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA113507-01/CA/NCI NIH HHS; R01 CA113507-03/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/D 21266; 0/RNA, Small Interfering; 0/temsirolimus; 107-73-3/Phosphorylcholine; 53123-88-9/Sirolimus; EC 2.7.-/Protein Kinases; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse; EC 2.7.1.137/PIK3CA protein, human; EC 2.7.11.1/Oncogene Protein v-akt |
| Comments/Corrections | |
Erratum In:
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Cancer Res. 2009 Oct 15;69(20):8216 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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