The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but LONG-term treatment also strips down mTORC2 in many cells, cutting Akt signaling. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Multiple human/mouse cell lines |
| Journal | Molecular Cell |
| Year | 2006 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.molcel.2006.03.029 · PMID 16603397 |
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.
| Intervention | Rapamycin (prolonged treatment) |
| Target | mTORC2 / Akt |
| Model | Multiple human/mouse cell lines |
| Effect | Prolonged rapamycin inhibits mTORC2 assembly and Akt/PKB in some cells – mTORC2 is not always rapamycin-insensitive |