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

Abstract

Loss of hepatic fructose-1, 6-bisphosphate aldolase B (Aldob) leads to a paradoxical up-regulation of glucose metabolism to favor hepatocellular carcinogenesis (HCC), 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 and tumor growth through a protein complex containing Aldob, Akt, and protein phosphatase 2A (PP2A), leading to inhibition of cell viability, cell cycle progression, glucose uptake, and metabolism. 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 down-regulation coupled with p-Akt up-regulation predicts a poor prognosis for HCC. We have further discovered that Akt inhibition or a specific small-molecule activator of PP2A (SMAP) efficiently attenuates HCC tumorigenesis in xenograft mouse models. Our work reveals a novel nonenzymatic role of Aldob in negative regulation of Akt activation, suggesting that directly inhibiting Akt activity or through reactivating PP2A may be a potential therapeutic approach for HCC treatment.

CPNE1 is a potential prognostic biomarker, associated with immune infiltrates and promotes progression of hepatocellular carcinoma

“…Previous studies have demonstrated that the AKT signaling pathway was activated in HCC and associated with multiple malignant biological behaviors of HCC, inhibition of AKT signaling inhibits the proliferation and migration of HCC [ 29 , 30 ]. In addition, P53 act as a tumor suppressor gene, lots of studies have shown that promoting P53 signaling could suppress the progression of hepatocellular carcinoma [ 31 , 32 ].…”

Fructose‐1,6‐Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis

“…Our recent study has demonstrated that ALDOB interacts with AKT to modulate AKT activity and loss of ALDOB activates AKT and promotes HCC by destabilizing the ALDOB/AKT/PP2A protein complex. ( 23 ) Thus, to dissect the different roles of ALDOB in direct binding with IR or through AKT on the downstream lipogenesis, we used ALDOB R46A and R43A mutants that showed differential propensity for interaction with IR and AKT, respectively (Fig. 1F).…”

Identification of a Hypoxia-Related Gene Signature for Predicting Systemic Metastasis in Prostate Cancer

“…Among the genes in the signature, ALDOB made the greatest contribution to the risk score. Previous studies have shown that the absence of ALDOB leads to the loss of Akt inhibition, promotes the development of cancer and indicates a poor prognosis ( Lian et al, 2019 ; Sun et al, 2019 ; He et al, 2020 ). This seems to be contrary to the conclusions of this study, but there are also studies that support the conclusions of this research.…”