PMID- 19047145
OWN - NLM
STAT- MEDLINE
DCOM- 20090116
LR  - 20161124
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 23
DP  - 2008 Dec 1
TI  - Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under 
      hypoxia are exerted through the Akt pathway.
PG  - 9678-85
LID - 10.1158/0008-5472.CAN-08-0969 [doi]
AB  - Malignant mesothelioma (MM) is a cancer of the lining of the lungs, heart, and 
      intestine and is known to respond poorly to chemotherapy. Here we show that 
      malignant mesothelial cells have an elevated Notch signaling pathway compared 
      with normal human mesothelial cells. We studied the role of Notch in MM under 
      normoxic and hypoxic conditions, the latter condition best recapitulating the MM 
      microenvironment. Genetic and chemical modulation of the Notch pathway indicated 
      that MM cells are dependent on Notch signaling. More specifically, this signaling 
      was Notch-1 dependent as the result of its negative transcriptional regulation on 
      phosphatase and tensin homologue (PTEN), which led to activation of the 
      prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of 
      rapamycin (mTOR) signaling pathway. Our study also provides evidence that whereas 
      Notch-1 is elevated in the malignant setting, Notch-2 is diminished. This 
      differential expression of the two Notch isoforms benefits cancer cell survival 
      because reexpression of Notch-2 was toxic to MM cells. The mechanism of Notch-2 
      toxicity to MM cells countered that of Notch-1, as it was the result of positive 
      transcriptional regulation of PTEN and inhibition of the PI3K/Akt/mTOR signaling 
      pathway. These results provide new insight into the role of Notch in MM and 
      suggest that Notch pathway inhibitors may be useful in the treatment of this 
      deadly disease.
FAU - Graziani, Irene
AU  - Graziani I
AD  - Department of Pathology and Oncology Institute, Loyola University Chicago, Cancer 
      Center, Maywood, Illinois 60153, USA.
FAU - Eliasz, Sandra
AU  - Eliasz S
FAU - De Marco, Melissa A
AU  - De Marco MA
FAU - Chen, Yuanbin
AU  - Chen Y
FAU - Pass, Harvey I
AU  - Pass HI
FAU - De May, Richard M
AU  - De May RM
FAU - Strack, Peter R
AU  - Strack PR
FAU - Miele, Lucio
AU  - Miele L
FAU - Bocchetta, Maurizio
AU  - Bocchetta M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (CDKN1A protein, human)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (NOTCH2 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Receptor, Notch2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Cell Growth Processes/physiology
MH  - Cell Hypoxia
MH  - Cell Survival/physiology
MH  - Cyclin-Dependent Kinase Inhibitor p21/metabolism
MH  - DNA, Neoplasm/biosynthesis
MH  - Humans
MH  - Mesothelioma/genetics/*metabolism/pathology
MH  - PTEN Phosphohydrolase/biosynthesis/genetics/metabolism
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Receptor, Notch1/antagonists & inhibitors/biosynthesis/*metabolism
MH  - Receptor, Notch2/biosynthesis/*metabolism
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
EDAT- 2008/12/03 09:00
MHDA- 2009/01/17 09:00
CRDT- 2008/12/03 09:00
PHST- 2008/12/03 09:00 [pubmed]
PHST- 2009/01/17 09:00 [medline]
PHST- 2008/12/03 09:00 [entrez]
AID - 68/23/9678 [pii]
AID - 10.1158/0008-5472.CAN-08-0969 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Dec 1;68(23):9678-85. doi: 10.1158/0008-5472.CAN-08-0969.