PMID- 17210710
OWN - NLM
STAT- MEDLINE
DCOM- 20070130
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 1
DP  - 2007 Jan 1
TI  - Nitric oxide in physiologic concentrations targets the translational machinery to 
      increase the proliferation of human breast cancer cells: involvement of mammalian 
      target of rapamycin/eIF4E pathway.
PG  - 289-99
AB  - Nitric oxide (NO) in nanomolar (nmol/L) concentrations is consistently detected 
      in tumor microenvironment and has been found to promote tumorigenesis. The 
      mechanism by which NO enhances tumor progression is largely unknown. In this 
      study, we investigated the possible mechanisms and identified cellular targets by 
      which NO increases proliferation of human breast cancer cell lines MDA-MB-231 and 
      MCF-7. DETA-NONOate, a long acting NO donor, with a half-life of 20 h, was used. 
      We found that NO (nmol/L) dramatically increased total protein synthesis in 
      MDA-MB-231 and MCF-7 and also increased cell proliferation. NO specifically 
      increased the translation of cyclin D1 and ornithine decarboxylase (ODC) without 
      altering their mRNA levels or half-lives. Critical components in the 
      translational machinery, such as phosphorylated mammalian target of rapamycin 
      (mTOR) and its downstream targets, phosphorylated eukaryotic translation 
      initiation factor and p70 S6 kinase, were up-regulated following NO treatment, 
      and inhibition of mTOR with rapamycin attenuated NO induced increase of cyclin D1 
      and ODC. Activation of translational machinery was mediated by NO-induced 
      up-regulation of the Raf/mitogen-activated protein/extracellular signal-regulated 
      kinase (ERK) kinase/ERK (Raf/MEK/ERK) and phosphatidylinositol 3-kinase (PI-3 
      kinase)/Akt signaling pathways. Up-regulation of the Raf/MEK/ERK and PI-3 
      kinase/Akt pathways by NO was found to be mediated by activation of Ras, which 
      was cyclic guanosine 3',5'-monophosphate independent. Furthermore, inactivation 
      of Ras by farnesyl transferase inhibitor or K-Ras small interfering RNA 
      attenuated NO-induced increase in proliferation signaling and cyclin D1 and ODC 
      translation, further confirming the involvement of Ras activation during 
      NO-induced cell proliferation.
FAU - Pervin, Shehla
AU  - Pervin S
AD  - Departments of Obstetrics and Gynecology and Molecular and Medical Pharmacology, 
      David Geffen School of Medicine at UCLA, University of California-Los Angeles, 
      10833 Le Conte Avenue, Los Angeles, CA, USA.
FAU - Singh, Rajan
AU  - Singh R
FAU - Hernandez, Estebes
AU  - Hernandez E
FAU - Wu, Guoyao
AU  - Wu G
FAU - Chaudhuri, Gautam
AU  - Chaudhuri G
LA  - eng
GR  - 1S06 GM 068510-03/GM/NIGMS NIH HHS/United States
GR  - CA 78357/CA/NCI NIH HHS/United States
GR  - G12 RR 03026/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Eukaryotic Initiation Factor-4E)
RN  - 0 (Nitroso Compounds)
RN  - 146724-94-9 (2,2'-(hydroxynitrosohydrazono)bis-ethanamine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 2.5.- (Alkyl and Aryl Transferases)
RN  - EC 2.5.1.- (p21(ras) farnesyl-protein transferase)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (raf Kinases)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Alkyl and Aryl Transferases/antagonists & inhibitors
MH  - Breast Neoplasms/genetics/*metabolism/*pathology
MH  - Cell Growth Processes/drug effects/physiology
MH  - Cell Line, Tumor
MH  - Cyclic GMP/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Eukaryotic Initiation Factor-4E/*metabolism
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - Nitric Oxide/*pharmacology
MH  - Nitroso Compounds/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Biosynthesis
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - raf Kinases/metabolism
EDAT- 2007/01/11 09:00
MHDA- 2007/01/31 09:00
CRDT- 2007/01/11 09:00
PHST- 2007/01/11 09:00 [pubmed]
PHST- 2007/01/31 09:00 [medline]
PHST- 2007/01/11 09:00 [entrez]
AID - 67/1/289 [pii]
AID - 10.1158/0008-5472.CAN-05-4623 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Jan 1;67(1):289-99. doi: 10.1158/0008-5472.CAN-05-4623.