PMID- 15634654
OWN - NLM
STAT- MEDLINE
DCOM- 20050517
LR  - 20211203
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 3
IP  - 12
DP  - 2004 Dec
TI  - Akt up-regulation increases resistance to microtubule-directed chemotherapeutic 
      agents through mammalian target of rapamycin.
PG  - 1605-13
AB  - Chemotherapeutic agents induce apoptosis in cancer cells through effects on 
      multiple intracellular targets. Recent observations suggest that a consistent 
      cellular response to chemotherapeutic agents of disparate classes is 
      down-regulation of glycolytic metabolism. Inhibition of glycolytic activity has 
      been linked to apoptotic induction in several models. The serine/threonine kinase 
      Akt (protein kinase B) promotes both glycolytic metabolism and survival, and 
      these functions have been shown to be linked. Because of its key role in both 
      glycolysis and survival, we examined the function of Akt in the cellular response 
      to cytotoxic agents. Following exposure to any of several chemotherapeutic 
      agents, an initial up-regulation in endogenous Akt activity is rapidly 
      suppressed. Using cells containing constitutively active myristoylated Akt, 
      dominant-negative kinase-dead Akt, or an empty vector control, we show here that 
      Akt activation markedly increases resistance to microtubule-directed agents, 
      including vincristine, colchicine, and paclitaxel. Akt also maintains increased 
      glycolytic rate in response to antimicrotubule treatment. Rapamycin inhibits 
      Akt-mediated maintenance of glycolysis and therapeutic resistance, indicating 
      that these effects are dependent on mammalian target of rapamycin (mTOR). 
      Furthermore, an activated mTOR mutant confers resistance to antimicrotubule 
      agents. Taken together, these observations suggest that activation of the 
      Akt-mTOR signaling pathway can augment glucose utilization and promote resistance 
      to chemotherapeutic agents that do not directly target metabolic regulation. 
      These data provide insight into potentially synergistic combinations of 
      anticancer therapies.
FAU - VanderWeele, David J
AU  - VanderWeele DJ
AD  - Committee on Cancer Biology, University of Chicago, Illinois, USA.
FAU - Zhou, Rixin
AU  - Zhou R
FAU - Rudin, Charles M
AU  - Rudin CM
LA  - eng
GR  - K08 CA81134/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Bcl2l1 protein, mouse)
RN  - 0 (Oligopeptides)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (bcl-X Protein)
RN  - 0I3V7S25AW (Myristic Acid)
RN  - 5J49Q6B70F (Vincristine)
RN  - 78VO7F77PN (arginyl-glycyl-aspartic acid)
RN  - EC 2.7.- (Protein Kinases)
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 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - P88XT4IS4D (Paclitaxel)
RN  - SML2Y3J35T (Colchicine)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Cycle/drug effects
MH  - Cells, Cultured
MH  - Colchicine/pharmacology
MH  - *Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - *Gene Expression Regulation
MH  - Genes, Dominant
MH  - Genetic Vectors
MH  - Glycolysis/drug effects
MH  - Hematopoietic Stem Cells/drug effects/metabolism
MH  - Membrane Potentials/drug effects
MH  - Mice
MH  - Microtubules/*drug effects/metabolism
MH  - Mitochondria/drug effects/metabolism
MH  - Mutation/genetics
MH  - Myristic Acid/metabolism
MH  - Oligopeptides/chemistry/metabolism
MH  - Paclitaxel/pharmacology
MH  - Protein Kinases/chemistry/genetics/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Vincristine/pharmacology
MH  - bcl-X Protein
EDAT- 2005/01/07 09:00
MHDA- 2005/05/18 09:00
CRDT- 2005/01/07 09:00
PHST- 2005/01/07 09:00 [pubmed]
PHST- 2005/05/18 09:00 [medline]
PHST- 2005/01/07 09:00 [entrez]
AID - 3/12/1605 [pii]
PST - ppublish
SO  - Mol Cancer Ther. 2004 Dec;3(12):1605-13.