PMID- 20124472
OWN - NLM
STAT- MEDLINE
DCOM- 20100407
LR  - 20211203
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 70
IP  - 4
DP  - 2010 Feb 15
TI  - The neurofibromatosis type 1 tumor suppressor controls cell growth by regulating 
      signal transducer and activator of transcription-3 activity in vitro and in vivo.
PG  - 1356-66
LID - 10.1158/0008-5472.CAN-09-2178 [doi]
AB  - Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome in 
      which affected individuals develop benign and malignant nerve tumors. The NF1 
      gene product neurofibromin negatively regulates Ras and mammalian target of 
      rapamycin (mTOR) signaling, prompting clinical trials to evaluate the ability of 
      Ras and mTOR pathway inhibitors to arrest NF1-associated tumor growth. To 
      discover other downstream targets of neurofibromin, we performed an unbiased 
      cell-based high-throughput chemical library screen using NF1-deficient malignant 
      peripheral nerve sheath tumor (MPNST) cells. We identified the natural product, 
      cucurbitacin-I (JSI-124), which inhibited NF1-deficient cell growth by inducing 
      apoptosis. We further showed that signal transducer and activator of 
      transcription-3 (STAT3), the target of cucurbitacin-I inhibition, was 
      hyperactivated in NF1-deficient primary astrocytes and neural stem cells, mouse 
      glioma cells, and human MPNST cells through Ser(727) phosphorylation, leading to 
      increased cyclin D1 expression. STAT3 was regulated in NF1-deficient cells of 
      murine and human origin in a TORC1- and Rac1-dependent manner. Finally, 
      cucurbitacin-I inhibited the growth of NF1-deficient MPNST cells in vivo. In 
      summary, we used a chemical genetics approach to reveal STAT3 as a novel 
      neurofibromin/mTOR pathway signaling molecule, define its action and regulation, 
      and establish STAT3 as a tractable target for future NF1-associated cancer 
      therapy studies.
FAU - Banerjee, Sutapa
AU  - Banerjee S
AD  - Department of Neurology, Mallinckrodt Institute of Radiology, Washington 
      University School of Medicine, St. Louis, Missouri 63110, USA.
FAU - Byrd, Jonathan N
AU  - Byrd JN
FAU - Gianino, Scott M
AU  - Gianino SM
FAU - Harpstrite, Scott E
AU  - Harpstrite SE
FAU - Rodriguez, Fausto J
AU  - Rodriguez FJ
FAU - Tuskan, Robert G
AU  - Tuskan RG
FAU - Reilly, Karlyne M
AU  - Reilly KM
FAU - Piwnica-Worms, David R
AU  - Piwnica-Worms DR
FAU - Gutmann, David H
AU  - Gutmann DH
LA  - eng
GR  - P50 CA094056/CA/NCI NIH HHS/United States
GR  - P50 CA94056/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100202
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Neurofibromin 1)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Triterpenes)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - SHQ47990PH (cucurbitacin I)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - *Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Chromones/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Genes, Tumor Suppressor/physiology
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Mice, Transgenic
MH  - Morpholines/pharmacology
MH  - Neurofibromin 1/genetics/*physiology
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - STAT3 Transcription Factor/antagonists & 
      inhibitors/genetics/*metabolism/physiology
MH  - Signal Transduction/drug effects/genetics
MH  - TOR Serine-Threonine Kinases
MH  - Triterpenes/pharmacology
MH  - Xenograft Model Antitumor Assays
PMC - PMC5534849
MID - NIHMS881655
COIS- Potential Conflicts of interest: None
EDAT- 2010/02/04 06:00
MHDA- 2010/04/08 06:00
PMCR- 2017/07/31
CRDT- 2010/02/04 06:00
PHST- 2010/02/04 06:00 [entrez]
PHST- 2010/02/04 06:00 [pubmed]
PHST- 2010/04/08 06:00 [medline]
PHST- 2017/07/31 00:00 [pmc-release]
AID - 0008-5472.CAN-09-2178 [pii]
AID - 10.1158/0008-5472.CAN-09-2178 [doi]
PST - ppublish
SO  - Cancer Res. 2010 Feb 15;70(4):1356-66. doi: 10.1158/0008-5472.CAN-09-2178. Epub 
      2010 Feb 2.