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

L Liu1, F Li, J A Cardelli

  • 1Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.

Oncogene
|May 23, 2006
PubMed

Insights

Rapamycin inhibits tumor cell motility by suppressing the S6 kinase 1 (S6K1) and 4E-binding protein 1 (4E-BP1) pathways. This action is a consequence of inhibiting mammalian target of rapamycin (mTOR) kinase activity, crucial for cell movement.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), is known to inhibit tumor cell motility.
  • The precise molecular mechanisms underlying this inhibition remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of mTOR signaling pathways in insulin-like growth factor I (IGF-I)-stimulated tumor cell motility.
  • To investigate the specific downstream effectors of mTOR involved in regulating cell motility.

Main Methods:

  • Utilized rapamycin and its analogs to study mTOR inhibition in various cell lines.
  • Employed RNA interference (RNAi) to downregulate key signaling proteins like raptor, rictor, S6 kinase 1 (S6K1), and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1).
  • Assessed cell motility in response to IGF-I stimulation and manipulation of mTOR pathway components.

Main Results:

  • Rapamycin inhibited IGF-I-stimulated cell motility, an effect dependent on mTOR kinase activity but not necessarily its kinase-dead mutant.
  • Downregulation of raptor, but not rictor, mimicked rapamycin's effect and inhibited S6K1 and 4E-BP1 phosphorylation.
  • Overexpression of a rapamycin-resistant S6K1 mutant conferred resistance to rapamycin's inhibitory effects on motility.
  • Downregulation of S6K1 or 4E-BP1 attenuated rapamycin's inhibition of IGF-I-stimulated motility.

Conclusions:

  • Both S6K1 and 4E-BP1 signaling pathways, regulated by mTOR complex 1 (TORC1), are essential for tumor cell motility.
  • Rapamycin inhibits IGF-I-stimulated cell motility by suppressing the S6K1 and 4E-BP1/eIF4E signaling cascades through the inhibition of mTOR kinase activity.

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