PMID- 17660507
OWN - NLM
STAT- MEDLINE
DCOM- 20080304
LR  - 20211203
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 28
IP  - 12
DP  - 2007 Dec
TI  - Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks 
      metastatic spread in a mouse model of thyroid cancer.
PG  - 2451-8
AB  - Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein 
      kinase B-signaling pathway has been associated with multiple human cancers, 
      including thyroid cancer. Recently, we showed that, similar to human thyroid 
      cancer, the PI3K-AKT pathway is overactivated in both the thyroid and metastatic 
      lesions of a mouse model of follicular thyroid carcinoma (TRbeta(PV/PV) mice). 
      This TRbeta(PV/PV) mouse harbors a knockin mutant thyroid hormone receptor beta 
      gene (TRbetaPV mutant) that spontaneously develops thyroid cancer and distant 
      metastasis similar to human follicular thyroid cancer. That the activation of the 
      PI3K-AKT signaling contributes to thyroid carcinogenesis raised the possibility 
      that this pathway could be a potential therapeutic target in follicular thyroid 
      carcinoma. The present study tested this possibility by treating TRbeta(PV/PV) 
      mice with LY294002 (LY), a potent and specific PI3K inhibitor, and evaluating the 
      effect of LY on the spontaneous development of thyroid cancer. LY treatment 
      inhibited the AKT-mammalian target of rapamycin (mTOR)-p70(S6K) signaling, and it 
      decreased cyclin D1 and increased p27(Kip1) expression to inhibit thyroid tumor 
      growth and reduce tumor cell proliferation. LY treatment increased caspase 3 and 
      decreased phosphorylated-BAD to induce apoptosis. In addition, LY treatment 
      reduced the AKT-matrix metalloproteinase 2 signaling to decrease cell motility to 
      block metastatic spread of thyroid tumors. Thus, these altered signaling pathways 
      converged effectively to prolong survival of TRbeta(PV/PV) mice treated with LY. 
      No significant adverse effects were observed for wild-type mice treated similarly 
      with LY. The present study provides the first preclinical evidence for the in 
      vivo efficacy for LY in the treatment of follicular thyroid cancer.
FAU - Furuya, Fumihiko
AU  - Furuya F
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, National Institutes of Health, Bethesda, MD 20892, USA.
FAU - Lu, Changxue
AU  - Lu C
FAU - Willingham, Mark C
AU  - Willingham MC
FAU - Cheng, Sheue-Yann
AU  - Cheng SY
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20070728
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Cdkn1b protein, mouse)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Thyroid Hormone Receptors beta)
RN  - 136601-57-5 (Cyclin D1)
RN  - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
SB  - IM
MH  - Adenocarcinoma, Follicular/*drug therapy/metabolism/secondary
MH  - Animals
MH  - Apoptosis
MH  - Caspase 3/metabolism
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Chromones/pharmacology/*therapeutic use
MH  - Cyclin D1/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p27/metabolism
MH  - Lung Neoplasms/drug therapy/secondary
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Mice
MH  - Mice, Mutant Strains
MH  - Morpholines/pharmacology/*therapeutic use
MH  - Neoplasm Invasiveness
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Thyroid Hormone Receptors beta/genetics/*metabolism
MH  - Thyroid Neoplasms/*drug therapy/metabolism/pathology
MH  - Tumor Cells, Cultured
EDAT- 2007/07/31 09:00
MHDA- 2008/03/05 09:00
CRDT- 2007/07/31 09:00
PHST- 2007/07/31 09:00 [pubmed]
PHST- 2008/03/05 09:00 [medline]
PHST- 2007/07/31 09:00 [entrez]
AID - bgm174 [pii]
AID - 10.1093/carcin/bgm174 [doi]
PST - ppublish
SO  - Carcinogenesis. 2007 Dec;28(12):2451-8. doi: 10.1093/carcin/bgm174. Epub 2007 Jul 
      28.