Research Article: Bioactive sphingolipid profile in a xenograft mouse model of head and neck squamous cell carcinoma

Date Published: April 19, 2019

Publisher: Public Library of Science

Author(s): Aiping Bai, Xiang Liu, Jacek Bielawski, Yusuf A. Hannun, Herve Le Stunff.


The purpose of this study was to determine the profile of bioactive sphingolipids in xenograft mouse tissues of head and neck squamous cell carcinoma. We utilized UHPLC-MS/MS to determine the profile of full set of ceramides, sphingosine, and sphingosine 1-phosphate in this xenograft mouse model. The tissues isolated and investigated were from brain, lung, heart, liver, spleen, kidney, bladder, tumors and blood. With the exception of equal volume of blood plasma (100ul), all tissues were studied with the same amount of protein (800ug). Results demonstrated that brain contained the highest level of ceramide and kidney had the highest level of sphingosine, whereas sphingosine 1-phosphate and dihydrosphingosine 1-phosphate were heavily presented in the blood. Brain also comprised the highest level of phospholipids. As for the species, several ceramides, usually present in very low amounts in cultured tumor cells, showed relatively high levels in certain tissues. This study highlights levels of bioactive sphingolipids profiles in xenograft mouse model of head and neck squamous cell carcinoma, and provides resources to investigate potential therapeutic targets and biomarkers that target bioactive sphingolipids metabolism pathways.

Partial Text

Bioactive sphingolipids (SL), which include ceramides (Cer), sphingoid bases, and their phosphates, make up the early products of the SL synthetic pathways. Cer, the central molecule, is associated with the action of several growth suppressor stimuli and inflammatory signals [1–3]. Cer can either be produced from complex SL or be synthesized (de novo pathway) from dihydroceramide (dhCer) under the catalysis of dhCer desaturase (DES1) [4]. Sphingoid bases are the fundamental building blocks of all SL. The main mammalian sphingoid bases are dihydrosphingosine (dhSph) and sphingosine (Sph). Sph has functional roles in regulating the actin cytoskeleton, endocytosis, cell cycle and apoptosis [5–6]. Cer can be hydrolyzed by ceramidase (CDase) to produce Sph. Sph is subsequently phosphorylated by Sph kinases (SKs) to generate Sph 1-phosphate (Sph 1-P), and Sph 1-P has a critical role in many physiological and pathophysiological processes, such as atherosclerosis, diabetes, and cancer et al [7–9].

To explore SL metabolism pathways that also have therapeutic benefits for cancer, we generated initial survey of bioactive SL species across the xenograft mouse tissues. Our data disclose an intricate tissue distribution of various species such that each tissue shows a unique SL profile, and most likely, the differences in levels are due to the expression levels of various SL metabolic enzymes, especially the Cer synthases [17,18]. The common Cer species that were represented in most of the tissues are C24:1-Cer (8/9) and C16-Cer (7/9). The only tissue that had C24:1-Cer below 10% is heart (9.1% of total, 182.9± 38.2 pmol). Interestingly, brain and plasma contained quite low levels of C16-Cer (2.2% in brain, 56.5±17.4 pmol; 4.9% in plasma, 11.5±2.7 pmol) as compared to the other 7 tissues that were investigated, while the highest level of C16-Cer was in kidney. We also observed 4 tissues contained relatively high level of C20-Cer whereas 3 tissues had high level of C18-Cer, and the highest level of C20-Cer was in heart, whereas C18-Cer was the most abundant Cer species in the brain.




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