Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and Mnk-mediated eukaryotic translation initiation factor 4E phosphorylation.
The initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, including those encoding oncogenic proteins. Therefore, eIF4E is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eIF4E (usually at Ser209) increases its binding affinity for the cap of mRNA and may also favor its entry into initiation complexes. Mammalian target of rapamycin (mTOR) inhibitors suppress cap-dependent translation through inhibition of the phosphorylation of eIF4E-binding protein 1. Paradoxically, we have shown that inhibition of mTOR signaling increases eIF4E phosphorylation in human cancer cells. In this study, we focused on revealing the mechanism by which mTOR inhibition increases eIF4E phosphorylation. Silencing of either mTOR or raptor could mimic mTOR inhibitors' effects to increase eIF4E phosphorylation. Moreover, knockdown of mTOR, but not rictor or p70S6K, abrogated rapamycin's ability to increase eIF4E phosphorylation. These results indicate that mTOR inhibitor-induced eIF4E phosphorylation is secondary to mTOR/raptor inhibition and independent of p70S6K. Importantly, mTOR inhibitors lost their ability to increase eIF4E phosphorylation only in cells where both Mnk1 and Mnk2 were knocked out, indicating that mTOR inhibitors increase eIF4E phosphorylation through a Mnk-dependent mechanism. Given that mTOR inhibitors failed to increase Mnk and eIF4E phosphorylation in phosphatidylinositol 3-kinase (PI3K)-deficient cells, we conclude that mTOR inhibition increases eIF4E phosphorylation through a PI3K-dependent and Mnk-mediated mechanism. In addition, we also suggest an effective therapeutic strategy for enhancing mTOR-targeted cancer therapy by cotargeting mTOR signaling and Mnk/eIF4E phosphorylation.
Wang
Xuerong
X
Department of Haematology, Emory University School of Medicine, 1365-C Clifton Road, C3088, Atlanta, GA 30322, USA.
Yue
Ping
P
Chan
Chi-Bun
CB
Ye
Keqiang
K
Ueda
Takeshi
T
Watanabe-Fukunaga
Rie
R
Fukunaga
Rikiro
R
Fu
Haian
H
Khuri
Fadlo R
FR
Sun
Shi-Yong
SY
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D039561:Eukaryotic Initiation Factor-4E; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C526292:IRS1 protein, human; C526295:Irs1 protein, mouse; C463659:RPTOR protein, human; C491395:MKNK1 protein, human; C106281:Mknk1 protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse