Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways

Li, Min; He, Xuxiao; Guo, Wei-Xing; Yu, Hongming; Zhang, Shicheng; Wang, Ningning; Liu, Guijun; Sa, Rina; Shen, Xia; Jiang, Yabo; Tang, Yufu; Zhuo, Yujuan; Yin, Cong; Tu, Qiaochu; Li, Nan; Nie, Xiaoqun; Liu, Yu; Hu, Zhimin; Zhu, Huarui; Ding, Jianping; Li, Zi; Liu, Te; Zhang, Fan; Zhou, He; Li, Shengxian; Yue, Jiang; Yan, Zheng; Cheng, Shuqun; Tao, Yongzhen; Yin, Huiyong

doi:10.1038/s43018-020-0086-7

Cited by 55 publications

(56 citation statements)

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“…Besides, the tricarboxylic acid (TCA) cycle is pivotal for oxidative phosphorylation in cells, producing ATP and the intermediates needed for macromolecule biosynthesis [ 4 , 52 ]. Our recent study revealed a novel mode of metabolic reprogramming of HCC due to the loss of hepatic aldolase B [ 31 ]. Emerging studies have demonstrated that not only glycolysis but also TCA cycle is a potential target for cancer therapy.…”

Section: Resultsmentioning

confidence: 99%

“…It is well-established that metabolic reprogramming has been regarded as a core hallmark of cancer, which sustains rapid proliferation and survival of cancer cells [ 8 , 16 ]. Our recent study has identified a novel metabolic reprogramming in HCC due to the loss of glycolytic enzyme aldolase B and targeting this metabolic pathway has potential therapeutic implications [ 31 ]. Taken together, our data clearly demonstrate that OPC-B2 directly inhibits AKT activity, leading to cell cycle arrest and reduced metabolic flux to glycolysis and TCA to suppress tumor growth.…”

Section: Discussionmentioning

confidence: 99%

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Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

et al. 2020

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The well-documented anticarcinogenic properties of natural polyphenolic proanthocyanidins (OPC) have been primarily attributed to their antioxidant and anti-inflammatory potency. Emerging evidence suggests that OPC may target canonical oncogenic pathways, including PI3K/AKT; however, the underlying mechanism and therapeutic potential remain elusive. Here we identify that proanthocyanidin B2 (OPC–B2) directly binds and inhibits AKT activity and downstream signalling, thereby suppressing tumour cell proliferation and metabolism in vitro and in a xenograft and diethyl-nitrosamine (DEN)-induced hepatocellular carcinoma (HCC) mouse models. We further find that OPC-B2 binds to the catalytic and regulatory PH domains to lock the protein in a closed conformation, similar to the well-studied AKT allosteric inhibitor MK-2206. Molecular docking and dynamic simulation suggest that Lys297 and Arg86 are critical sites of OPC-B2 binding; mutation of Lys297 or Arg86 to alanine completely abolishes the antitumor effects of OPC-B2 but not MK-2206. Together, our study reveals that OPC-B2 is a novel allosteric AKT inhibitor with potent anti-tumour efficacy beyond its antioxidant and anti-inflammatory properties.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

et al. 2020

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“…Aldob has been documented to be down-regulated in HCC tissues in transcriptomic and proteomic studies, which is correlated with multiple malignant characteristics of HCC [15][16][17]. The mechanism underlying the paradoxical loss of Aldob and up-regulated glycolysis in HCC tumor cells has not been defined until our recent study identified a novel tumor-suppressive mechanism by which Aldob directly binds and inhibits the rate-limiting enzyme in pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase (G6PD) [18]. Loss of Aldob releases G6PD activity and up-regulates PPP metabolism to bypass the disrupted glycolysis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

PLoS Biol

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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.

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“…Down-regulation of hepatic HK1 and HK2 leads to the impairment of glucose uptake and metabolism and HCC cell proliferation [21,54,55]. Indeed, our studies showed a prominent elevation of entire central carbon metabolism in liver tumor tissues of ALDOB KO mice compared to WT mice, including glycolysis, TCA, and PPP [18], which was accompanied by activated Akt and increased expression of HK1 and HK2, suggesting that Aldob deficiency facilitates glucose uptake and metabolic flux through up-regulation of hexokinases to sustain tumor growth. Moreover, Aldob-induced inhibition of Akt activity not only reduced glucose uptake and metabolic flux to glycolysis and TCA cycle, but also induced cell cycle arrest through down-regulating Akt/ GSK3β/CyclinD1 signaling, thereby leading to the impairment of cell proliferation.…”

Section: Plos Biologymentioning

confidence: 56%

“…Our recent study has revealed a novel tumor suppressive role for the glycolytic enzyme Aldob in HCC through directly binding to G6PD and inhibiting its activity, acting as a metabolic switch in glucose metabolism and regulating the metabolic reprogramming [18]. Accumulating body of evidence has demonstrated that metabolic reprogramming in cancer cells to meet increased bioenergetic and biosynthetic requirements during tumorigenesis depends on multiple intracellular signaling pathways [19].…”

Section: Aldob Expression Is Negatively Correlated With Akt Activatiomentioning

confidence: 99%

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Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways

Cited by 55 publications

References 54 publications

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity

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

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