Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB.
The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types.
Sarbassov
Dos D
DD
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.
Ali
Siraj M
SM
Sengupta
Shomit
S
Sheen
Joon-Ho
JH
Hsu
Peggy P
PP
Bagley
Alex F
AF
Markhard
Andrew L
AL
Sabatini
David M
DM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011233:Precipitin Tests; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014157:Transcription Factors; D014183:Transplantation, Heterologous
D000903:Antibiotics, Antineoplastic; C504923:Crtc2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus