PMID- 18566221
OWN - NLM
STAT- MEDLINE
DCOM- 20080822
LR  - 20211203
IS  - 1535-7163 (Print)
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 7
IP  - 6
DP  - 2008 Jun
TI  - Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible 
      factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under 
      hypoxia in lung cancer cell lines.
PG  - 1506-13
LID - 10.1158/1535-7163.MCT-07-2334 [doi]
AB  - Down-regulation by small interfering RNA or absence of hypoxia-inducible factor 
      (HIF-1alpha) has been shown to lead to increased sensitivity to glycolytic 
      inhibitors in hypoxic tumor cells. In surveying a number of tumor types for 
      differences in intrinsic levels of HIF under hypoxia, we find that the reduction 
      of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) 
      correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung 
      cancer cell lines when treated under hypoxia. Because HIF-1alpha translation is 
      regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an 
      analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR 
      and AKT activity and found that HIF-1alpha down-regulation coincided with 
      increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG 
      toxicity in cell lines that did not express HIF. These results support the 
      hypothesis that although mTOR inhibition leads to the blockage of numerous 
      downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells 
      through down-regulation of HIF-1alpha. Overall, our findings show that CCI-779 
      hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic 
      expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, 
      may be important in dictating the decision on how best to use 2-DG alone or in 
      combination with CCI-799 to kill hypoxic tumor cells clinically.
FAU - Wangpaichitr, Medhi
AU  - Wangpaichitr M
AD  - Department of Molecular Cell Biology and Anatomy, Miller School of Medicine, 
      University of Miami, Miami, FL 33101, USA.
FAU - Savaraj, Niramol
AU  - Savaraj N
FAU - Maher, Johnathan
AU  - Maher J
FAU - Kurtoglu, Metin
AU  - Kurtoglu M
FAU - Lampidis, Theodore J
AU  - Lampidis TJ
LA  - eng
GR  - R01 CA037109/CA/NCI NIH HHS/United States
GR  - R01 CA037109-19/CA/NCI NIH HHS/United States
GR  - R01CA037109/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.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Small Interfering)
RN  - 624KN6GM2T (temsirolimus)
RN  - 9G2MP84A8W (Deoxyglucose)
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  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Cell Hypoxia/drug effects
MH  - Cell Line, Tumor
MH  - Deoxyglucose/*pharmacology
MH  - Down-Regulation/drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Lung Neoplasms/*enzymology/pathology
MH  - Mutation/genetics
MH  - Protein Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - RNA, Small Interfering/pharmacology
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
PMC - PMC2587287
MID - NIHMS54490
EDAT- 2008/06/21 09:00
MHDA- 2008/08/23 09:00
PMCR- 2009/06/01
CRDT- 2008/06/21 09:00
PHST- 2008/06/21 09:00 [pubmed]
PHST- 2008/08/23 09:00 [medline]
PHST- 2008/06/21 09:00 [entrez]
PHST- 2009/06/01 00:00 [pmc-release]
AID - 7/6/1506 [pii]
AID - 10.1158/1535-7163.MCT-07-2334 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2008 Jun;7(6):1506-13. doi: 10.1158/1535-7163.MCT-07-2334.