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Relieving autophagy and 4EBP1 from rapamycin resistance

Nyfeler, Beat and Bergman, Phillip and Triantafellow, Ellen and Wilson, Christopher and Zhu, Yanyi and Radetich, Branko and Finan, Peter and Klionsky, Daniel and Murphy, Leon (2011) Relieving autophagy and 4EBP1 from rapamycin resistance. Molecular and Cellular Biology, 31 (14). pp. 2867-2876. ISSN 0270-7306

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is a multiprotein signaling complex regulated by oncogenes and tumor suppressors. Outputs downstream of mTORC1 include ribosomal protein S6 kinase 1 (S6K1), eukaryotic translation initiation factor 4E (eIF4E) and autophagy, and their modulation leads to changes in cell growth, proliferation and metabolism. Rapamycin, an allosteric mTORC1 inhibitor, does not antagonize equally these outputs, but the reason for this is unknown. Here, we show that the ability of rapamycin to activate autophagy in different cell lines correlates with mTORC1 stability. Rapamycin exposure destabilizes mTORC1, but in cell lines where autophagy is drug-insensitive, higher levels of mTOR-bound raptor are detected, as compared to cells where rapamycin stimulates autophagy. Using siRNA we find that knockdown of raptor relieves autophagy and the eIF4E effector pathway from rapamycin resistance. Importantly, non-efficacious concentrations of an ATP-competitive mTOR inhibitor can be combined with rapamycin to synergistically inhibit mTORC1, activate autophagy, but leave mTORC2 signaling intact. These data suggest that partial inhibition of mTORC1 by rapamycin can be overcome using combination strategies and offer a therapeutic avenue to achieve complete and selective inhibition of mTORC1.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); but on personal or university-hosted websites only
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3431

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