Figure 5. Targeting 6PGD activates AMPK and represses ACC1 and mTOR pathways.
(A) Schematic showing key metabolic pathways downstream of the pentose phosphate pathway (PPP). By suppressing AMPK signalling, the PPP can enhance the activity of ACC1 and mTOR and subsequently various growth-promoting anabolic processes. (B) S3 activates AMPK and inhibits ACC1 and mTOR signalling. LNCaP (left) and VCaP (right) cells were treated for 24 hr with the indicated doses of S3 prior to analysis of indicated proteins by immunoblotting. (C) S3 inhibits mTOR signalling, as indicated by reduced pS6, in patient-derived explants (PDEs). PDEs (from n = 11 patients) were treated for 72 hr. The levels of pS6 were measured using immunohistochemistry (IHC). Boxes (graph on left) show minimum and maximum (bottom and top lines, respectively) and mean (line within the boxes) values. A paired t test was used to compare Ki67 positivity in treated versus vehicle-treated control samples (***p<0.001). Representative IHC images are shown on the right (scale bars represent 50 µm).
Figure 5—figure supplement 1. 6PGD knockdown inhibits ACC1 and mTOR signalling, as determined by increased levels of pACC1 and decreased levels of pS6/pS6K, respectively.
