PMID- 21445973
OWN - NLM
STAT- MEDLINE
DCOM- 20120227
LR  - 20181201
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 130
IP  - 4
DP  - 2012 Feb 15
TI  - Long-term exposure of gastrointestinal stromal tumor cells to sunitinib induces 
      epigenetic silencing of the PTEN gene.
PG  - 959-66
LID - 10.1002/ijc.26095 [doi]
AB  - Although sunitinib possesses significant clinical effects on imatinib-resistant 
      gastrointestinal stromal tumors (GISTs), the individuals with GIST eventually 
      become resistant to treatment with this tyrosine kinase inhibitor. The mechanism 
      of resistance to sunitinib is still under investigation. To address this issue, 
      we have established sunitinib-resistant GIST-T1 sublines (designated as GIST-T1R) 
      by culturing cells with increasing concentrations of sunitinib. GIST-T1R cells 
      were also resistant to imatinib-mediated growth inhibition. Examination of 
      intracellular signaling found that Akt/ mammalian target of rapamycin (mTOR) 
      signaling remained activated in GIST-T1R but not in parental GIST-T1 cells, after 
      exposure of these cells to sunitinib, as measured by immunoblotting. Further 
      study found that the phosphatase and tensin homolog deleted on chromosome ten 
      (PTEN) gene was silenced by methylation of the promoter region of the gene. 
      Notably, forced-expression of PTEN in GIST-T1R cells negatively regulated the 
      Akt/mTOR pathways and sensitized these cells to sunitinib-mediated growth arrest 
      and apoptosis. Taken together, epigenetic silence of PTEN might be one of the 
      mechanisms which cause drug-resistance in individuals with GIST after exposure to 
      tyrosine kinase inhibitors. Blockade of the PI3K/Akt signaling with the specific 
      inhibitors could be useful in such a case.
CI  - Copyright (c) 2011 UICC.
FAU - Yang, Jing
AU  - Yang J
AD  - Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi 
      University, Nankoku, Kochi, Japan.
FAU - Ikezoe, Takayuki
AU  - Ikezoe T
FAU - Nishioka, Chie
AU  - Nishioka C
FAU - Takezaki, Yuka
AU  - Takezaki Y
FAU - Hanazaki, Kazuhiro
AU  - Hanazaki K
FAU - Taguchi, Takahiro
AU  - Taguchi T
FAU - Yokoyama, Akihito
AU  - Yokoyama A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110618
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Indoles)
RN  - 0 (Piperazines)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - V99T50803M (Sunitinib)
SB  - IM
MH  - Antineoplastic Agents/*therapeutic use
MH  - Benzamides
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - *Epigenesis, Genetic
MH  - Gastrointestinal Neoplasms/*drug therapy/genetics
MH  - Gastrointestinal Stromal Tumors/*drug therapy/genetics
MH  - Humans
MH  - Imatinib Mesylate
MH  - Indoles/*therapeutic use
MH  - PTEN Phosphohydrolase/*antagonists & inhibitors/genetics
MH  - Piperazines/therapeutic use
MH  - Pyrimidines/therapeutic use
MH  - Pyrroles/*therapeutic use
MH  - Sunitinib
EDAT- 2011/03/30 06:00
MHDA- 2012/03/01 06:00
CRDT- 2011/03/30 06:00
PHST- 2010/04/26 00:00 [received]
PHST- 2011/03/16 00:00 [accepted]
PHST- 2011/03/30 06:00 [entrez]
PHST- 2011/03/30 06:00 [pubmed]
PHST- 2012/03/01 06:00 [medline]
AID - 10.1002/ijc.26095 [doi]
PST - ppublish
SO  - Int J Cancer. 2012 Feb 15;130(4):959-66. doi: 10.1002/ijc.26095. Epub 2011 Jun 
      18.