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

doi:10.1371/journal.pbio.3000803

	Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex
	He, Xuxiao 1,2; Li, Min 1,2; Yu, Hongming 3; Liu, Guijun 1,2; Wang, Ningning 1,2; Yin, Chunzhao2,4 ; Tu, Qiaochu2,4 ; Narla, Goutham 5; Tao, Yongzhen 1; Cheng, Shuqun 3; Yin, Huiyong1,2,4,6
	2020-12
发表期刊	PLOS BIOLOGY (IF:7.8[JCR-2023],8.2[5-Year])
ISSN	1544-9173
卷号	18 期号:12
发表状态	已发表
DOI	10.1371/journal.pbio.3000803
摘要	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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收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[31671231][32030053][91857112] ; National Key R&D Program of China[2018YFA0800300][2016YFD0400205]
WOS研究方向	Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
WOS类目	Biochemistry & Molecular Biology ; Biology
WOS记录号	WOS:000597167900001
出版者	PUBLIC LIBRARY SCIENCE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/124771
专题	生命科学与技术学院_硕士生生命科学与技术学院_特聘教授组_尹慧勇组生命科学与技术学院_博士生
通讯作者	Tao, Yongzhen; Cheng, Shuqun; Yin, Huiyong
作者单位	1.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Nutr Metab & Food Safety, Shanghai, Peoples R China 2.Chinese Acad Sci, Univ Chinese Acad Sci, Beijing, Peoples R China 3.Eastern Hepatobiliary Surg Hosp, Shanghai, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 5.Univ Michigan, Dept Int Med, Div Genet Med, Ann Arbor, MI 48109 USA 6.Minist Hlth, Key Lab Food Safety Risk Assessment, Beijing, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	He, Xuxiao,Li, Min,Yu, Hongming,et al. Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex[J]. PLOS BIOLOGY,2020,18(12).
APA	He, Xuxiao.,Li, Min.,Yu, Hongming.,Liu, Guijun.,Wang, Ningning.,...&Yin, Huiyong.(2020).Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex.PLOS BIOLOGY,18(12).
MLA	He, Xuxiao,et al."Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex".PLOS BIOLOGY 18.12(2020).