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Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

Oncogene volume 25, pages 7029–7040 (2006)Cite this article

Abstract

Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits tumor cell motility. However, the underlying mechanism is poorly understood. Here, we show that rapamycin inhibited type I insulin-like growth factor (IGF-I)-stimulated motility of a panel of cell lines. Expression of a rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) decreased cell motility. However, only downregulation of raptor mimicked the effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. Cells infected with an adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing wild-type S6K1, or a control virus, conferred to resistance to rapamycin. Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of cell motility. In contrast, expression of constitutively active 4E-BP1 dramatically inhibited IGF-I-stimulated cell motility. The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition of mTOR kinase activity.

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Acknowledgements

We thank Drs Robert T Abraham, Jun Chung, Peter J Houghton, John C Lawrence, David M Sabatini for providing cell lines or constructs. We are also grateful to Drs Peter J Houghton and Robert E Rhoads for their critical reading of this paper and helpful discussions. This work was supported in part by a Feist-Weiller Cancer Research Award (SH) and a Start-up Fund (SH) jointly from Louisiana State University Health Sciences Center in Shreveport, LA, USA.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    L Liu, F Li & S Huang

  2. Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    J A Cardelli

  3. Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    J A Cardelli & S Huang

  4. Department of Surgery, Dartmouth Medical School, Lebanon, NH, USA

    K A Martin

  5. Department of Cell Biology, Harvard Medical School, Boston, MA, USA

    J Blenis

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Correspondence to S Huang.

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Liu, L., Li, F., Cardelli, J. et al. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 25, 7029–7040 (2006). https://doi.org/10.1038/sj.onc.1209691

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