Both mTORC1 and mTORC2 are involved in the regulation of cell adhesion

Abstract

mTOR is a central controller for cell growth/proliferation and survival. Recent studies have shown that mTOR also regulates cell adhesion, yet the underlying mechanism is not known. Here we found that inhibition of mTOR by rapamycin reduced the basal or type I insulin-like growth factor (IGF-1)-stimulated adhesion of cancer cells. Further research revealed that both mTORC1 and mTORC2 were involved in the regulation of cell adhesion, as silencing expression of raptor or rictor inhibited cell adhesion. Also, PP242, an mTORC1/2 kinase inhibitor, inhibited cell adhesion more potently than rapamycin (mTORC1 inhibitor). Of interest, ectopic expression of constitutively active and rapamycin-resistant mutant of p70 kinase 1 (S6K1) or downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) conferred resistance to rapamycin inhibition of cell adhesion, whereas expression of constitutively hypophosphorylated 4E-BP1 (4EBP1-5A) or downregulation of S6K1 suppressed cell adhesion. In contrast, neither genetic manipulation of Akt activity nor pharmacological inhibition of Akt affected cell adhesion. The results suggest that both mTORC1 and mTORC2 are involved in the regulation of cell adhesion; and mTORC1 regulates cell adhesion through S6K1 and 4E-BP1 pathways, but mTORC2 regulates cell adhesion via Akt-independent mechanism.

Resveratrol inhibits Erk1/2‐mediated adhesion of cancer cells via activating PP2A–PTEN signaling network

“…This prompted us to study whether inhibition of mTOR can potentiate the inhibitory effect of resveratrol on IGF-1induced inhibition of PP2A-PTEN and activation of Akt-Erk1/2, as well as cell adhesion. We found that treatment with rapamycin alone inhibited p-S6K1 but induced p-Akt (Figure 7a,b), which is line with our previous observations (L. Chen, Xu, et al, 2015). It has been proposed that rapamycin inhibits S6K1, which may activate Akt through a S6K1-IRS negative feedback mechanism (Cornu, Albert, & Hall, 2013;Lamming, Ye, Sabatini, & Baur, 2013).…”

“…As shown in Figure 7a,b, rapamycin or resveratrol alone obviously suppressed the basal and IGF-1-stimulated de-PP2Ac, p-PP2Ac, p-PTEN, and p-Erk1/2 in the cells. In line with previous observations (L. Chen, Xu, et al, 2015), rapamycin inhibited p-S6K1 and induced p-Akt. However, rapamycin potentiated the inhibitory effects of resveratrol on IGF-1-stimulated de-PP2Ac, p-PP2Ac, p-PTEN, and p-Erk1/2.…”

“…Increasing findings have shown that resveratrol can inhibit mTOR (Widlund et al, 2013). Importantly, we have demonstrated that mTOR is involved in the regulation of cell adhesion (L. Chen, Xu, et al, 2015). To determine whether inhibition of mTOR co-operates with resveratrol in activating PP2A and PTEN, leading to more inhibition of Erk1/2 and cancer cell adhesion, Rh30 and HeLa cells were pretreated with or without the mTORC1 inhibitor rapamycin (100 ng/ml) for 1 hr, and then treated with or without resveratrol (100 μM) for 4 hr, followed by incubation with or without IGF-1 (10 ng/ml) for 1 hr.…”

“…2.4 | Lentiviral short hairpin RNA (shRNA) cloning, production, and infection Lentiviral shRNAs to Erk1/2, mTOR, and GFP (for control) were generated and used as described ( L. Chen, Xu, et al, 2015;L. Chen, Liu, Luo, & Huang, 2008).…”

Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer

“…Tumor cell adhesion, motility, and invasion capability are also regulated by mTORC1 and mTORC21516. Their kinase activities are negatively regulated by DEPTOR, which is a recently identified mTOR binding protein17.…”