PMID- 16317089
OWN - NLM
STAT- MEDLINE
DCOM- 20060113
LR  - 20211203
IS  - 1541-7786 (Print)
IS  - 1541-7786 (Linking)
VI  - 3
IP  - 11
DP  - 2005 Nov
TI  - Mammalian target of rapamycin promotes vincristine resistance through multiple 
      mechanisms independent of maintained glycolytic rate.
PG  - 635-44
AB  - Deregulation of the phosphoinositide 3-kinase-Akt pathway is a major contributor 
      to oncogenesis and resistance to cancer therapy. Recent work has shown mammalian 
      target of rapamycin (mTOR) to be a major target downstream of Akt that 
      contributes to both transformation and therapeutic resistance. Although 
      inhibitors of Akt are not yet clinically available, rapamycin, a mTOR-specific 
      inhibitor, has long been used as an immunosuppressant, and several rapamycin 
      analogues are now in clinical trials in oncology. Recent data indicate that a 
      mTOR complex phosphorylates Akt, and this complex is insensitive to rapamycin. We 
      show that dominant-negative mTOR diminishes phosphorylation of endogenous Akt and 
      exogenous myristoylated Akt (mAkt), that prolonged exposure to rapamycin also 
      inhibits Akt activation, and that this inhibition is dependent on new protein 
      synthesis. These data suggest that mTOR facilitates Akt activation through 
      mechanisms other than direct phosphorylation. A constitutively active mTOR mutant 
      that fails to enhance Akt phosphorylation nevertheless promotes resistance to 
      multiple antimicrotubule agents, indicating that mTOR also mediates survival 
      independent of Akt. Although Akt- and mTOR-mediated survival has been linked to 
      regulation of cellular metabolism, we also show that survival and metabolic 
      control are separable. The hexokinase inhibitor 5-thioglucose markedly inhibits 
      glycolytic rate but does not diminish vincristine resistance mediated by mAkt or 
      mTOR, and it has only a minor effect on mTOR- or mAkt-mediated resistance to 
      growth factor withdrawal, suggesting that Akt-mTOR-mediated resistance is largely 
      independent of maintenance of glycolytic rate. We conclude that mTOR activity can 
      promote resistance through multiple mechanisms independent of maintained 
      glycolytic rate.
FAU - Vanderweele, David J
AU  - Vanderweele DJ
AD  - Committee on Cancer Biology, University of Chicago, Chicago, IL, USA.
FAU - Rudin, Charles M
AU  - Rudin CM
LA  - eng
GR  - K08 CA81134/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 3PRV1384UO (5-thio-D-glucose)
RN  - 5J49Q6B70F (Vincristine)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - IY9XDZ35W2 (Glucose)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - Cell Line
MH  - Drug Resistance, Neoplasm/*physiology
MH  - Glucose/analogs & derivatives/pharmacology
MH  - *Glycolysis/drug effects
MH  - Hexokinase/metabolism
MH  - Lactic Acid/metabolism
MH  - Liver/cytology
MH  - Mice
MH  - Microtubules/metabolism
MH  - Mutagenesis
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Vincristine/*pharmacology
EDAT- 2005/12/01 09:00
MHDA- 2006/01/18 09:00
CRDT- 2005/12/01 09:00
PHST- 2005/12/01 09:00 [pubmed]
PHST- 2006/01/18 09:00 [medline]
PHST- 2005/12/01 09:00 [entrez]
AID - 3/11/635 [pii]
AID - 10.1158/1541-7786.MCR-05-0063 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2005 Nov;3(11):635-44. doi: 10.1158/1541-7786.MCR-05-0063.