An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1
- An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1
- Thoreen, Carson C.; Kang, Seong A.; Chang, Jae Won; Liu, Qingsong; Zhang, Jianming; Gao, Yi; Reichling, Laurie J.; 심태보; Sabatini, David M.; Gray, Nathanael S.
- mTor; kinase; cancer; Rapamycin; inhibitor
- Issue Date
- The Journal of biological chemistry
- VOL 284, NO 12, 8023-8032
- The mammalian target of rapamycin (mTOR) kinase is the
catalytic subunit of two functionally distinct complexes,
mTORC1and mTORC2, that coordinately promote cell growth,
proliferation, and survival. Rapamycin is a potent allosteric
mTORC1inhibitor with clinical applications as an immunosuppressant
and anti-cancer agent. Here we find that Torin1, a
highly potent and selective ATP-competitive mTOR inhibitor
that directly inhibits both complexes, impairs cell growth and
proliferation to a far greater degree than rapamycin. Surprisingly,
these effects are independent of mTORC2 inhibition and
are instead because of suppression of rapamycin-resistant functions
of mTORC1 that are necessary for cap-dependent translation
and suppression of autophagy. These effects are at least
partly mediated by mTORC1-dependent and rapamycin-resistant
phosphorylation of 4E-BP1. Our findings challenge the
assumption that rapamycin completely inhibits mTORC1 and
indicate that direct inhibitors of mTORC1 kinase activity may
be more successful than rapamycin at inhibiting tumors that
depend on mTORC1.
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