Document Detail


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.
MedLine Citation:
PMID:  19706758     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Dingxie Liu; Peng Hou; Zhi Liu; Guojun Wu; Mingzhao Xing
Related Documents :
17792088 - Threads in the hagfish slime gland thread cells: organization, biochemical features, an...
18038758 - Human submandibular gland (hsg) cell line as a model for studying salivary gland ca2+ s...
1343998 - Histochemical classification of human minor labial salivary glands according to their g...
11196468 - Daily regeneration of rat adrenocortical cells: circadian and zonal variations in cytog...
7995518 - Intercellular c-signaling and the traveling waves of myxococcus.
7637558 - The effect of two synthetic phospholipids on cell proliferation and phosphatidylcholine...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-08-25
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-16     Completed Date:  2009-10-07     Revised Date:  2014-07-10    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7311-9     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
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:
R01 CA113507/CA/NCI NIH HHS; R01 CA113507-01/CA/NCI NIH HHS; R01 CA113507-03/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/RNA, Small Interfering; 0/temsirolimus; 107-73-3/Phosphorylcholine; 2GWV496552/perifosine; 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; W36ZG6FT64/Sirolimus
Comments/Corrections
Erratum In:
Cancer Res. 2009 Oct 15;69(20):8216

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international...
Next Document:  Genomic alterations in tumor stroma.