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Liu L, Li F, Cardelli JA, Martin KA, Blenis J, Huang S.
Oncogene. 2006 Nov 9;25(53):7029-40.
Rapamycin inhibits cell motility by suppression of mTOR-mediated
S6K1 and 4E-BP1 pathways.
Department of Biochemistry and Molecular Biology, Louisiana State
University Health Sciences Center, Shreveport, LA 71130-3932, USA
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.
PMID: 16715128
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