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Journal article
Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis
Journal of translational medicine, Vol.22, pp.1-15
2024
PMID: 38200582
Appears in Cancer Research Cluster Research Collection
Abstract
Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation.
Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells.
SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner.
This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.
Details
- Title
- Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis
- Authors
- Xin Tracy Liu (Author) - The University of SydneyYu Huang (Author) - The University of SydneyDa Liu (Author) - The University of SydneyYingxin Celia Jiang (Author) - The University of SydneyMin Zhao (Author) - University of the Sunshine Coast, Queensland, Centre for BioinnovationLong Hoa Chung (Author) - The University of SydneyXingxing Daisy Han (Author) - The University of SydneyYinan Zhao (Author) - Dalian Minzu UniversityJinbiao Chen (Author) - The University of SydneyPaul Coleman (Author) - The University of SydneyKa Ka Ting (Author) - The University of SydneyCollin Tran (Author) - The University of SydneyYingying Su (Author) - The University of SydneyClaude Vincent Dennis (Author) - Royal Prince Alfred HospitalAtul Bhatnagar (Author) - The University of SydneyKen Liu (Author) - Royal Prince Alfred HospitalAnthony Simon Don (Author) - The University of SydneyMathew Alexander Vadas (Author) - The University of SydneyMark Douglas Gorrell (Author) - Royal Prince Alfred HospitalShubiao Zhang (Author) - Dalian Minzu UniversityMichael Murray (Author) - The University of SydneyMary Meltem Kavurma (Author) - The Heart Research InstituteGeoffrey William McCaughan (Author) - Royal Prince Alfred HospitalJennifer Ruth Gamble (Author) - The University of SydneyYanfei Qi (Corresponding Author) - The University of Sydney
- Publication details
- Journal of translational medicine, Vol.22, pp.1-15
- Publisher
- BioMed Central Ltd.
- Date published
- 2024
- DOI
- 10.1186/s12967-023-04830-z
- ISSN
- 1479-5876
- PMID
- 38200582
- Copyright note
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
- Grants
- Organisation Unit
- Cancer Research Cluster; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99996895902621
- Output Type
- Journal article
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