Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing Aldob/Akt/PP2A protein complex

Abstract

Loss of hepatic fructose-1, 6-bisphosphate aldolase B (Aldob) leads to a paradoxical upregulation of glucose metabolism to favor hepatocellular carcinogenesis but the upstream signaling events remain poorly defined. Akt is highly activated in HCC and targeting Akt is being explored as a potential therapy for HCC. Herein we demonstrate that Aldob suppresses Akt activity through a protein complex containing Aldob, Akt, and protein phosphatase 2A (PP2A), leading to inhibition of cell viability, cell cycle progression, glucose metabolism and tumor growth. Interestingly, Aldob directly interacts with phosphorylated Akt (p-Akt) and promotes the recruitment of PP2A to dephosphorylate p-Akt, and this scaffolding effect of Aldob is independent of its enzymatic activity. Loss of Aldob or disruption of Aldob/Akt interaction in Aldob R304A mutant restores Akt activity and tumor promoting effects. Consistently, Aldob and p-Akt expression are inversely correlated in human HCC tissues, and Aldob downregulation coupled with p-Akt upregulation predicts a poor prognosis for HCC. We have further discovered that a specific small-molecule activator of PP2A (SMAP) efficiently attenuates HCC tumorigenesis in Aldob-deficient cell lines and xenografts. Our work reveals a novel non-glycolytic role of Aldob in negative regulation of Akt activation, suggesting that inhibiting Akt activity and reactivating PP2A may be a potential therapeutic approach for HCC treatment.