Abstract #4648: Rapamycin inhibits tube formation of lymphatic endothelial cells by targeting TORC1-mediated expression of Flt4

Studies have shown that rapamycin, a selective inhibitor of the mammalian target of rapamycin (mTOR), inhibits lymphangiogenesis. However, the underlying mechanism is largely not known. Here we show that insulin-like growth factor-1 (IGF-1) and 2% fetal bovine serum (FBS) stimulated tube formation in human and mouse lymphatic endothelial cells (LEC), which was inhibited by rapamycin. Treatment of the cells with rapamycin for 48 h downregulated the basal or IGF-1/FBS-stimulated expression of Flt-4 (also named VEGFR-3), a critical molecule involved in lymphangiogenesis. Expression of a rapamycin-resistant mutant of mTOR (S2025I, mTORrr), but not a kinase-dead (D2038A) mTORrr, conferred resistance to rapamycin inhibition of Flt-4 expression and tube formation. Disruption of TORC1 by silencing expression of raptor, mimicking the effect of rapamycin, prevented IGF-1 or FBS-stimulated Flt-4 expression and tube formation. Downregulation of p70 S6 kinase 1 (S6K1) or expression of constitutively active eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) (4EBP1-5A) inhibited IGF-1 or FBS-stimulated Flt-4 expression and tube formation, whereas expression of constitutively active S6K1 or downregulation of 4E-BP1 conferred resistance to rapamycin inhibition of Flt-4 expression and tube formation. The results indicate that rapamycin inhibits tube formation of lymphatic endothelial cells by targeting TORC1-mediated Flt-4 expression.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4648.