Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9).

Autor: Athavale D; 1Laboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, 411 007 India., Chouhan S; 1Laboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, 411 007 India., Pandey V; 1Laboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, 411 007 India.; 2Present address: Laboratory of Neuroscience, Department of Biotechnology & Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana 500046 India., Mayengbam SS; 1Laboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, 411 007 India., Singh S; 1Laboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, 411 007 India., Bhat MK; 1Laboratory No. 6, National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune, 411 007 India.
Jazyk: angličtina
Zdroj: Cancer & metabolism [Cancer Metab] 2018 Oct 25; Vol. 6, pp. 16. Date of Electronic Publication: 2018 Oct 25 (Print Publication: 2018).
DOI: 10.1186/s40170-018-0187-2
Abstrakt: Background: PCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (HCC) has been documented; however, the underlying cause and implications of such dyslipidemia remain unclear.
Methods: The present study includes the use of HepG2 tumor xenograft model to study the potential role of glucose (by providing 15% glucose via drinking water) in regulating PCSK9 expression and associated hypercholesterolemia. To support in vivo findings, in vitro approaches were used by incubating HCC cells in culture medium with different glucose concentrations or treating the cells with glucose uptake inhibitors. Impact of hypercholesterolemia on chemotherapy was demonstrated by exogenously providing LDLc followed by appropriate in vitro assays.
Results: We observed that serum and hepatic PCSK9 level is decreased in mice which were provided with glucose containing water. Interestingly, serum and tumor PCSK9 level was upregulated in HepG2-tumor-bearing mice having access to water containing glucose. Additionally, elevated LDLc is detected in sera of these mice. In vitro studies indicated that PCSK9 expression was increased by high glucose availability with potential involvement of reactive oxygen species (ROS) and sterol regulatory element binding protein-1 (SREBP-1). Furthermore, it is also demonstrated that pre-treatment of cells with LDLc diminishes cytotoxicity of sorafenib in HCC cells.
Conclusion: Taken together, these results suggest a regulation of PCSK9 by high glucose which could contribute, at least partly, towards understanding the cause of hypercholesterolemia in HCC and its accompanied upshots in terms of altered response of HCC cells towards cancer therapy.
Competing Interests: All animal experiments were performed as per the requirement and guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India, and after obtaining permission of the Institutional Animal Ethics Committee (IAEC).Not applicableThe authors declare that they have no competing interest.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Databáze: MEDLINE
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