Document Detail


Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin.
MedLine Citation:
PMID:  15634654     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
David J VanderWeele; Rixin Zhou; Charles M Rudin
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  3     ISSN:  1535-7163     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2005-01-06     Completed Date:  2005-05-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1605-13     Citation Subset:  IM    
Affiliation:
Committee on Cancer Biology, University of Chicago, Illinois, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents, Phytogenic / pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cells, Cultured
Colchicine / pharmacology
Drug Resistance, Neoplasm*
Drug Synergism
Gene Expression Regulation*
Genes, Dominant
Genetic Vectors
Glycolysis / drug effects
Hematopoietic Stem Cells / drug effects,  metabolism
Membrane Potentials / drug effects
Mice
Microtubules / drug effects*,  metabolism
Mitochondria / drug effects,  metabolism
Mutation / genetics
Myristic Acid / metabolism
Oligopeptides / chemistry,  metabolism
Paclitaxel / pharmacology
Protein Kinases / chemistry,  genetics,  metabolism*
Protein-Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism
Signal Transduction / drug effects
Sirolimus / pharmacology
Vincristine / pharmacology
bcl-X Protein
Grant Support
ID/Acronym/Agency:
K08 CA81134/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Bcl2l1 protein, mouse; 0/Oligopeptides; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-X Protein; 33069-62-4/Paclitaxel; 53123-88-9/Sirolimus; 544-63-8/Myristic Acid; 57-22-7/Vincristine; 64-86-8/Colchicine; 99896-85-2/arginyl-glycyl-aspartic acid; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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