Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex
Open Access
- 4 December 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 18 (12), e3000803
- https://doi.org/10.1371/journal.pbio.3000803
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.Funding Information
- National Natural Science Foundation of China (32030053)
- National Natural Science Foundation of China (31671231)
- National Natural Science Foundation of China (91857112)
- National Key R&D Program of China (2018YFA0800300)
- National Key R&D Program of China (2016YFD0400205)
This publication has 71 references indexed in Scilit:
- Cancer cell metabolism: implications for therapeutic targetsExperimental & Molecular Medicine, 2013
- Determinants for Substrate Specificity of Protein Phosphatase 2AEnzyme Research, 2011
- Retracted: Antitumor effects of OSU‐2S, a nonimmunosuppressive analogue of FTY720, in hepatocellular carcinomaJournal of Hepatology, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Regulation of cancer cell metabolismNature Reviews Cancer, 2011
- Regulation of the mTOR Complex 1 Pathway by Nutrients, Growth Factors, and StressMolecular Cell, 2010
- Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intoleranceJournal of Inherited Metabolic Disease, 2010
- Is Akt the “Warburg kinase”?—Akt-energy metabolism interactions and oncogenesisSeminars in Cancer Biology, 2009
- HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and ProliferationCancer Cell, 2007
- On the Origin of Cancer CellsScience, 1956