Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 31;24(3):2652.
doi: 10.3390/ijms24032652.

The Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism

Ling-Yu Tian  1 , Daniel J Smit  1 , Manfred Jücker  1
Affiliations
Review

The Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism

Ling-Yu Tian et al. Int J Mol Sci. .

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Metabolic reprogramming is considered a new hallmark of cancer, but it remains unclearly described in HCC. The dysregulation of the PI3K/AKT/mTOR signaling pathway is common in HCC and is, therefore, a topic of further research and the concern of developing a novel target for liver cancer therapy. In this review, we illustrate mechanisms by which this signaling network is accountable for regulating HCC cellular metabolism, including glucose metabolism, lipid metabolism, amino acid metabolism, pyrimidine metabolism, and oxidative metabolism, and summarize the ongoing clinical trials based on the inhibition of the PI3K/AKT/mTOR pathway in HCC.

Keywords: HCC treatment; amino acid metabolism; cancer therapy; glucose metabolism; lipid metabolism; oxidative metabolism; pyrimidine metabolism; tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of interaction between the PI3K/AKT/mTOR pathway and glucose metabolism in HCC. Lamc1, laminin subunit gamma 1; NDFIP1, Nedd4 family-interacting protein 1; G6PD, glucose 6 phosphate dehydrogenase; PKM2, pyruvate kinase M2; LDHA, lactate dehydrogenase; HK2, hexokinase 2; GLUT1, glucose transporter 1; 4EBP1, eIF4E binding protein.
Figure 2
Figure 2
Interplay between the PI3K/AKT/mTOR signaling and lipid metabolism in HCC. Abbreviation: ACC, acetyl-CoA-carboxylase; FASN, fatty acid synthase; SREBP1, sterol regulatory-element binding proteins 1; RPS6, ribosomal protein S6; COX-2, cyclooxygenase 2; NRF2, nuclear factor erythroid 2-related factor 2; SREBP2, sterol regulatory-element binding proteins 2.
Figure 3
Figure 3
Regulation of the glutamine metabolism of the PI3K/AKT/mTOR pathway. Abbreviation: GLS1, Glutaminase 1; Nqo1, NAD(P)H quinone dehydrogenase 1; SIRT4, Sirtuin 4; GS, Glutamine synthetase; GDH, Glutamine dehydrogenase.
Figure 4
Figure 4
The role of PI3K/AKT/mTOR signaling in regulating pyrimidine metabolism. Abbreviation: VIPR1, vasoactive intestinal polypeptide type-I receptor; UBE2T, ubiquitin conjunction enzyme E2T; CAD, carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase; DHODH, dihydroorotate dehydrogenase; UMPS, uridine 5′-monophosphate synthase; E2F1, E2F transcription factor 1; GSK3β, glycogen synthase kinase 3 beta; CDK4/6, cyclin-dependent kinase 4/6.
Figure 5
Figure 5
The crosstalk between the PI3K/AKT/mTOR axis and the oxidative metabolism. Abbreviation: HBx, hepatitis B virus x protein; ROS, reactive oxygen species; MCUR1, mitochondrial calcium uniporter regulator 1.
Figure 6
Figure 6
The clinical trial of targeting PI3K/AKT/mTOR pathway on progress based on the Table 2.
See this image and copyright information in PMC

References

    1. Choo S.P., Tan W.L., Goh B.K.P., Tai W.M., Zhu A.X. Comparison of hepatocellular carcinoma in Eastern versus Western populations. Cancer. 2016;122:3430–3446. doi: 10.1002/cncr.30237. - DOI - PubMed
    1. Zheng Y.L., Li L., Jia Y.X., Zhang B.Z., Li J.C., Zhu Y.H., Li M.Q., He J.Z., Zeng T.T., Ban X.J., et al. LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway. Theranostics. 2019;9:796–810. doi: 10.7150/thno.28992. - DOI - PMC - PubMed
    1. Forner A., Reig M., Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–1314. doi: 10.1016/S0140-6736(18)30010-2. - DOI - PubMed
    1. Faubert B., Solmonson A., DeBerardinis R.J. Metabolic reprogramming and cancer progression. Science. 2020;368:5473. doi: 10.1126/science.aaw5473. - DOI - PMC - PubMed
    1. Yeh Y.C., Ho H.L., Wu Y.C., Pan C.C., Wang Y.C., Chou T.Y. AKT1 internal tandem duplications and point mutations are the genetic hallmarks of sclerosing pneumocytoma. Mod. Pathol. 2020;33:391–403. doi: 10.1038/s41379-019-0357-y. - DOI - PubMed

MeSH terms

Substances