Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML.
The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation. This resulted in suppression of phosphorylation of the direct AKT substrate FKHR and decreased transcription of D-cyclins in AML cells. Similar observations were made in samples from patients with hematologic malignancies who received RDs in clinical studies. Our study provides the first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and supports the therapeutic potential of mTOR inhibition strategies in leukemias.
Zeng
Zhihong
Z
Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Sarbassov
Dos D
dos D
Samudio
Ismael J
IJ
Yee
Karen W L
KW
Munsell
Mark F
MF
Ellen Jackson
C
C
Giles
Francis J
FJ
Sabatini
David M
DM
Andreeff
Michael
M
Konopleva
Marina
M
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism*; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D000068338:Everolimus; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic / Q000187:drug effects; D020298:U937 Cells
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056741:Cyclin D; D016213:Cyclins; D051272:Glucose Transporter Type 1; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011506:Proteins; C492571:RICTOR protein, human; D012333:RNA, Messenger; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; C495677:SLC2A1 protein, human; C401859:temsirolimus; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus