Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): Attenuation of C18-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis

Abstract

It has been documented previously that defects in the generation of C(18)-ceramide, a product of ceramide synthase 1 (CerS1), also known as longevity assurance gene 1 (hLASS1), play important roles in the pathogenesis and/or progression of HNSCC. However, whether altered levels of ceramide generation in HNSCC tumors have any clinical relevance remains unknown. In this study, the levels of endogenous ceramides were measured in tumor tissues of 45 HNSCC patients as compared to their normal tissues using high-pressure liquid chromatography/mass spectrometry (LC/MS), and then possible link between ceramide levels and the clinical parameters of HNSCC were examined. The data showed that the levels of C(16)-, C(24)-, C(24:1)-ceramides were significantly elevated in the majority of tumor tissues compared to their normal tissues, while the levels of only C(18)-ceramide were significantly decreased in HNSCC tumors, especially in tumor tissues of male patients. Importantly, it was also shown here that decreased C(18)-ceramide levels in HNSCC tumor tissues were significantly associated with the higher incidences of lymphovascular invasion, and pathologic nodal metastasis. Importantly, attenuation of C(18)-ceramide was also positively linked to the higher overall stages of the primary HNSCC tumors. Therefore, these data suggest, for the first time, that the defects in the generation/accumulation of C(18)-ceramide might have important clinical roles in HNSCC, especially in lymphovascular invasion and nodal disease.

Palmitate increases sphingosine-1-phosphate in C2C12 myotubes via upregulation of sphingosine kinase message and activity

“…by guest, on May 11, 2018 www.jlr.org Downloaded from never been determined in these systems. Since recent studies indicate different functional roles for different ceramide species ( 24,36,37 ), determining ceramides produced under these conditions may shed light on sphingolipid-dependent pathology associated with excess PAL. Indeed, LC/MS data revealed specifi city in dihycroceramide profi les.…”

Alteration of Ceramide Synthase 6/C16-Ceramide Induces Activating Transcription Factor 6-mediated Endoplasmic Reticulum (ER) Stress and Apoptosis via Perturbation of Cellular Ca2+ and ER/Golgi Membrane Network

“…Results in Increased Tumor Growth in SCID Mice-Our previous studies unexpectedly showed that knockdown of CerS6 resulted in apoptosis, suggesting a pro-survival role (21), consistent with increased CerS6/C 16 -ceramide in the majority of primary HNSCC tumors compared with adjacent non-cancerous head and neck tissues (27). To investigate the possible prosurvival role of CerS6-generated C 16 -ceramide, we first examined the growth of UM-SCC-22A cell-derived xenografts in SCID mice, which were stably transfected with tetracyclineinducible lentiviral expression vectors containing WT or the catalytically inactive H212A mutant of CerS6, which does not generate C 16 -ceramide.…”

Silencing of CerS6 increases the invasion and glycolysis of melanoma WM35, WM451 and SK28 cell lines via increased GLUT1-induced downregulation of WNT5A

“…CerS1-dependent generation of C18-ceramide plays important roles in the pathogenesis of head and neck squamous cell carcinoma (HNSCC) (29,30). Additionally, as an important member of the CerS family, various studies also suggest that CerS6 is involved in cancer etiology.…”