Inhibition of S6 kinase suppresses the apoptotic effect of eIF4E ablation by inducing TGF-β-dependent G1 cell cycle arrest

► Rapamycin induces apoptosis in cancer cells by indirect inhibition of eIF4E through suppression of 4E-BP1 phosphorylation. ► The apoptotic effect of rapamycin occurs in the absence of serum - in the presence of serum, rapamycin induces G1 arrest. ► In contrast with rapamycin, suppression of eIF4E expression causes apoptosis in both the absence and presence of serum. ► In addition to suppressing 4E-BP1 phosphorylation, rapamycin suppresses phosphorylation of the mTORC1 substrate S6 kinase. ► Suppression of both S6 kinase and 4E-BP1 phosphorylation leads to G1 arrest in the presence of serum and prevents apoptosis.