fig8

Figure 8. Proposed model for synergistic action of statins and APi CHR2863. (A) Peptide breakdown by aminopeptidases provides amino acids for re-utilization in protein synthesis. According to previously described models^{[49-51,56,62,63,66]}, an increased intralysomal amino acid content triggers dissociation of V-ATPase and Ragulator-Rag-mTORC1 complex. Binding of the latter complex to (prenylated) Rheb (in the lysosomal membrane) and membrane association of Ragulator will then induce mTOR activation and initiation of protein synthesis; (B) Inhibition of aminopeptidases by CHR2863 (or bestatin) will reduce the intralysomal amino acid content and dissociation of the Ragulator-Rag complex from mTORC1. By a different mechanism, statins may block Rheb prenylation and abolish its lysosomal membrane localization. The combined effect of CHR2863 and statins may then synergize in impairing mTOR activation, protein synthesis and inhibiting cell growth. The figure was created via BioRender. APi: Aminopeptidase inhibitor; CHR2863: (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester.