Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition

The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepi...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Vol. 65; no. 16; p. 7052
Main Authors: Sun, Shi-Yong, Rosenberg, Laura M, Wang, Xuerong, Zhou, Zhongmei, Yue, Ping, Fu, Haian, Khuri, Fadlo R
Format: Journal Article
Language:English
Published: United States 15.08.2005
Subjects:
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - enzymology
Carcinoma, Non-Small-Cell Lung - metabolism
Cell Growth Processes - drug effects
Cell Line, Tumor
Chromones - administration & dosage
Enzyme Activation
Eukaryotic Initiation Factor-4E - metabolism
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - enzymology
Lung Neoplasms - metabolism
Morpholines - administration & dosage
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation - drug effects
Protein Kinase Inhibitors - pharmacology
Protein Kinases - metabolism
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Signal Transduction - drug effects
Sirolimus - administration & dosage
Sirolimus - pharmacology
TOR Serine-Threonine Kinases
ISSN:0008-5472
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Summary:The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepithelial neoplasia. However, many cancer cells are resistant to rapamycin and its derivatives. The mechanism of this resistance remains a subject of major therapeutic significance. Here we report that the inhibition of mTOR by rapamycin triggers the activation of two survival signaling pathways that may contribute to drug resistance. Treatment of human lung cancer cells with rapamycin suppressed the phosphorylation of p70S6 kinase and 4E-BP1, indicating an inhibition of mTOR signaling. Paradoxically, rapamycin also concurrently increased the phosphorylation of both Akt and eIF4E. The rapamycin-induced phosphorylation of Akt and eIF4E was suppressed by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002, suggesting the requirement of PI3K in this process. The activated Akt and eIF4E seem to attenuate rapamycin's growth-inhibitory effects, serving as a negative feedback mechanism. In support of this model, rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells. Thus, our study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor.
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ISSN:0008-5472
DOI:10.1158/0008-5472.can-05-0917